Novel prostaglandins

ABSTRACT

This disclosure describes novel 15-hydroxy prostanoic acid derivatives having anti-ulcer, bronchodilator, and hypotensive activity.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of our copending applicationSer. No. 719,650, filed Sept. 1, 1976, which is in turn a Divisional ofour application Ser. No. 555,219, filed Mar. 4, 1975, now U.S. Pat. No.3,993,674, which is in turn a Divisional of our application Ser. No.353,152, filed Apr. 20, 1973 now U.S. Pat. No. 3,884,969.

BRIEF SUMMARY OF THE INVENTION

This invention relates to novel 15-hydroxy prostanoic acids andderivatives, as well as to intermediates and methods for theirpreparation. The novel prostanoic acids and derivatives of thisinvention may be represented by the following general formula: ##STR1##wherein Y is a divalent radical selected from the group consisting ofthose of the formulae: ##STR2## and Z is a divalent radical selectedfrom the group consisting of those of the formulae: ##STR3## wherein mis an integer from 3 to 8, inclusive, p is an integer from 2 to 6inclusive, R₄ is an alkyl group having up to 3 carbon atoms, and R₅ isan alkyl group having up to 3 carbon atoms, a fluorine atom or a phenylgroup; the moiety --C₁₃ --C₁₄ -- is ethylene, or trans-vinylene; R₁ isselected from the group consisting of lower alkyl groups having up to 3carbon atoms; R₂ is selected from the group consisting of hydrogen,triphenylmethyl, and mono- or di-methoxy substituted triphenylmethyl; R₃is hydroxyl or alkoxy having from one to twelve carbon atoms; R₇ isselected from the group consisting of hydrogen and lower alkyl groupshaving up to 3 carbon atoms with the proviso that when R₇ is alkyl thenR₂ is hydrogen; n is an integer having the value one or two; s is zeroor an integer having the value one to five inclusive, t is zero or one;and R is selected from the group consisting of cycloalkyl groups havingfrom three to nine carbon atoms; cycloalkenyl groups having from five tonine carbon atoms; mono or dilower alkyl substituted cycloalkyl groupshaving from three to eight carbon atoms in the ring, mono or diloweralkyl substituted cycloalkenyl groups having from five to eight carbonatoms in the ring and adamantyl groups; with the proviso that only onedouble bond or cyclopropyl group can be immediately adjacent to C₁₅ ;and with the additional proviso that when n is one, Z is --(CH₂)_(m) --and R is a saturated cycloalkyl or adamantyl group then the sum of s andt is at least one.

DETAILED DESCRIPTION OF THE INVENTION

Also embraced within the scope of the present invention are thenon-toxic, pharmaceutically acceptable salts of the novel compounds ofthe present invention when R₃ is hydroxy. The cations comprised in thesesalts include, for example, the non-toxic metal cations such as thesodium ion, potassium ion, calcium ion, and magnesium ion as well as theorganic amine cations such as the tri(lower alkyl)amine cations (e.g.,triethylamine, tri(β-hydroxyethyl)amine, procaine and the like).

The compounds of this invention include all possible optical isomers.The novel compounds of the present invention are usually obtainable asoils having characteristic absorption spectra. They are relativelyinsoluble in water but are relatively soluble in common organic solventssuch as ethanol, ethyl acetate, dimethylformamide, and the like. Thecationic salts of the compounds when R₃ is hydroxy are, in general,white to yellow crystalline solids having characteristic melting pointsand absorption spectra. They are relatively soluble in water, methanol,and ethanol but are relatively insoluble in benzene, diethyl ether andpetroleum ether.

The novel compounds of the present invention may be readily preparedfrom certain cycloalkenone intermediates some of which may berepresented by the following general formula: ##STR4## wherein Z and nare as defined above, and R'₃ has all the possibilities given above forR₃ except that it is not hydroxyl. The preparation of certain of thesecycloalkenones is described in Belgium Pat. No. 786,215 (granted andopened to inspection Jan. 15, 1973). Others of the requisitecycloalkenones are prepared by extension of the methods describedtherein.

The preparation of the cycloalkenone intermediates (X, XI) bearing a cisdouble bond in the carboxylic acid side chain can be accomplished by thesequences illustrated in Flowsheets A or B. In Flowsheet A whichfollows, n and p are as hereinabove defined. ##STR5##

In the above Flowsheet A, the sequence wherein a2-carbalkoxycycloalkanone (I) is transformed to a2-(β-hydroxyethyl)cycloalk-2-en-1-one (VII) is carried out in the mannerdescribed in Belgium Pat. No. 786,215 citered hereinabove. Methyl ethercleavage of the corresponding 2-(β-methoxyethyl)cycloalkenone isachieved by treating with boron tribromide. Oxidation of the alcoholwith Collins reagent (chromium trioxide-pyridine complex) in methylenechloride under anhydrous conditions provides the aldehyde (VIII), whichis then treated in anhydrous dimethylsulfoxide with the ylid (IX)prepared from an (ω-carboxyalkyl)triphenyl phosphonium bromide andsodium hydride. The use of dimethylsulfoxide as a solvent for thisreaction leads to the predominant formation of the desired cis doublebond in (X). The acid function in (X) can be esterified in the usualfashion; with diazomethane, the methyl ester (XI) is obtained.

Cyclopentenones such as (XVI) may also be prepared by the sequenceillustrated in Flowsheet B, which follows and in which p is ashereinabove defined. ##STR6##

In Flowsheet B, above the bicyclic hemiacetal (XII) [P. A. Grieco,Journ. Org. Chem., 37, 2363 (1972)] is treated with ylid (XIII) to givethe 1-hydroxy-3-cyclopentene (XIV). Oxidation with Jones reagent givesthe corresponding ketone (XV), which on base treatment furnishes therequired cyclopentenone (XVI), which can then by esterified in the usualmanner.

The 9-keto-13-trans-prostenoic acids and esters of this invention may beprepared by the novel conjugate addition process outlined in theFlowsheet C which follows. In Flowsheets C, R, R₁, Z, R₃, R'₃, n, s andt are as defined hereinabove; R₈ is a lower alkyl group (each of thethree R₈ radicals bonded to an aluminum atom does not necessarily haveto be the same), R'₂ has all the possibilities given hereinabove for R₂except hydrogen, and R' has all the possibilities given hereinabove forR except that it does not include cycloalkenyl, cyclopropyl or adamantylgroups. ##STR7##

In accordance with the reaction scheme of Flowsheet C, acetylene (XVII)is treated with a cycloalkyl, or a cycloalkyl substituted alkyl acidchloride (XVIII) in the presence of aluminum trichloride to provide the1-chloro-3-keto-trans-1-alkene (XIX). Interchange with sodium iodide,preferably in a ketone solvent such as acetone, provides thecorresponding trans-vinyl iodide (XX). Reduction of the keto function in(XX) with sodium borohydride furnishes the alcohol (XXII), which is thenblocked with the triphenylmethyl group or a triphenylmethyl groupsubstiuted with one or two methoxy groups. Introduction of the methoxygroup(s) increases the rate of etherification and more importantlyincreases the facility by which acid hydrolysis later cleaves thetrityloxy group. Blocking the hydroxy function can also be accomplishedwith a trialkylsilyl group, a tetrahydropyranyl group, α-alkoxyethylgroup or any other hydroxy blocking group compatible with the conjugateaddition process described below and which can later be removed byconditions to which the final products (XXIX) are stable.

Alternatively, trans-1-alkenyl iodide (XXII) can be obtained from thealdehyde (XXIII) by reaction of (XXIII) with lithio acetylide andtreatment of the resulting 3-hydroxy terminal acetylene (XXIV) withdisiamylborane followed with trimethylamine oxide and then with iodineand sodium hydroxide solution.

Submission of the blocked vinyl iodide (XXI) to metal interchange withan alkyl lithium e.g. n-butyl lithium, at very low temperatures, e.g.-78° C., provides the vinyl lithium derivative (XXV), thetrans-configuration of the double bond being retained. After one to fourhours, addition of a trialkyl aluminum, preferably trimethyl aluminum,to the solution of the lithio derivative (XXV) furnishes the key alanateintermediate (XXVI), also with retention of the trans-configuration ofthe double bond. The cycloalkenone (XXVII) dissolved in ether or othernon-prototropic solvent, is then added to the alanate solution. Theresulting solution is allowed to warm to room temperature and is keptfor about six to eighteen hours at ambient temperatures. The carboxylicacid group in cycloakenone (XXVII) is blocked as an ester. Interactionof alanate (XXVI) with cycloalkenone (XXVII) results in the transfer ofthe trans-1-alkenyl ligand in (XXVI) with retention of thetrans-configuration to the cycloalkenone (XXVII) furnishing, afterquenching the reaction solution, the 1,4-conjugate addition product(XXVIII). In (XXVIII) we are not certain of the relative configurationof the side-chains to each other. The situation is indicated instructure (XXVIII) by the bond between the ring and the ##STR8## chainand is indicated in the nomenclature of the compounds involved by thedesignation 8ξ. In any event deblocking to (XXIX) with acid, e.g.treatment with acetic acid:tetrahydrofuran:water in the ratio of 3:1:1at 35°-45° C. for some three to forty-eight hours, results in thetrans-relationship between the chains. This procedure results inde-O-tritylation as well as hydrolysis of tetrahydropyranyl andtrialkylsilyl groups. Alkyl esters are not cleaved by this procedure.Saponification can be accomplished by the usual alkaline procedures.

In order to ensure a trans-relationship in (XXVIII) these products canbe submitted to conditions known in the literature to equilibratecis-8-iso PGE₁ to a mixture containing about 90% of the trans product.These conditions involve treatment with potassium acetate in aqueousmethanol for 96 hours at room temperature.

The 13-dihydro derivatives (C₁₃ -C₁₄ is ethylene) of this invention canbe prepared by reduction of the Δ¹³ function in the corresponding13-prostenoic acids or esters. This reduction can be accomplished bycatalytic reduction, preferably at low pressure with a noble metalcatalyst in an inert solvent at ambient temperatures.

The 13-dihydro derivatives can also be prepared by treatingcycloalkenones of formula (XXVII) with Grignard reagent (XXX) in theusual manner in the presence of a catalyst such as the tributylphosphinecuprous iodide complex. The 15-O-t-butyl blocking group in the conjugateaddition product can be efficiently removed by treatment with neattrifluoroacetic acid in the cold for about twenty minutes followed bybrief treatment with aqueous ammonia because of potential15-O-trifluoracetylation. ##STR9##

The 9-keto derivatives of this invention can be converted to thecorresponding 9-hydroxy derivatives. If this conversion is effected withsodium borohydride, the product is a mixture of 9α- and 9β-hydroxyderivatives (XXXII) and (XXXIII), respectively as set forth in thefollowing reaction scheme of Flowsheet D which follows and in which Z,R₃, n, s, t, R, R₆, R₇ and C₁₃ -C₁₄ are as hereinabove defined.

When the reduction of the 9-keto function is carried out with lithiumperhydro-9-boraphenyalkyl hydride [H. C. Brown and W. C. Dickason,Journ. Amer. Chem. Sec., 92 709 (1970)] the product is at leastpredominantly the 9α-hydroxy derivative (XXXII), wherein the 9-hydroxygroup is cis to the side-chain attached to C₈ and to the 11-substituentif present. In accordance with accepted convention, an α-substituent atthe 8-, 9-, 11- or 12-positions is behind the plane of the paper whereasa β-substitutent at these positions is in front of the plane of thepaper. This is usually represented by a - - - bond for an α-substituent,a bond for a β-substituent, and a bond where both are indicated.##STR10##

A useful procedure for the introduction of the 15-lower alkyl group (R₇)is illustrated by the sequences of Flowsheet E, which follows. ##STR11##

In Flowsheet E above R, R₁, R'₃, R₇ n, s, t and Z are as hereinabovedefined. In the sequence depicted in Flowsheet E the 9,15-diol (XXXIV)is treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (XXXV), whichpreferentially oxidizes the allylic alcohol function at C₁₅ to give the15-keton (XXXVI). Blocking of the remaining hydroxy function as atrimethylsilyl ether gives (XXXVII) which is reacted with the alkylGrignard, R₇ MgI, to give the 15-alkyl-15-hydroxy derivative (XXXVIII).Hydrolysis of the silyl ether blocking group then furnishes the diolester (XXXIX), saponification of which gives (XLI). Oxidation of thesecondary 9-hydroxy function in (XXXIX) provides the 15-alkyl-9-oxoester (XL), saponification of which furnishes (XLII).

This procedure leads to two epimeric C₁₅ alcohols and these areseparable by chromatograhic procedures.

This invention also embraces the novel and useful intermediatesillustrated by the generic formula A below, in which R'₂, s, t, R₁ and Rare as hereinabove defined with the only proviso being that when R is a3-numbered carbocycle the sume of s and t is at least one; and K isiodine, lithium, or lithio tri (lower alkyl) aluminate ##STR12##

The novel compounds of the present invention have potential utility ashypotensive agents, anti-ulcer agents, agents for the treatment ofgastric hypersecretion and gastric erosion, periodontal disease,glacoma, uveitis, bronchodilators, antimicrobial agents,anticonvulsants, abortifacients, agents for the induction of labor,agents for the induction of menses, fertility-controlling agents,central nervous system regulatory agents, salt and water-retentionregulatory agents, diuretics, fat metabolic regulatory agents,serum-cholesterol lowering agents, anti-inflammatory agents and asagents for the inhibition of platelet aggregation. Certain of the novelcompounds of this invention possess utility as intermediates for thepreparation of other of the novel compounds of this invention.

The compounds of this invention provide protection against theulcerogenic properties of indomethacin. This assay was carried out inthe following manner.

Rats were starved for 48 hours (water was given ad libitum).Indomethacin (20 mg./kg. of body weight) was administered by thesubcutaneous route and one-half the dose of the test compound wasadministered by gavage at the same time. After three hours, the secondhalf of the test compound was administered also be gavage. Five hoursafter the administration of indomethacin the animals were decapitatedand the stomachs removed. The stomachs were washed with distilled water,blotted on gauze, cut along the larger curvature, and the contentsrinsed with distilled water. The stomachs were spread out, pinned on acork and visualized under magnifying glass for ulcers. The criteria forscoring of ulcers was as previously reported. [Abdel-Galil et al. Brit.J. Pharmac. Chemotherapy 33:1-14 (1968)].

Score

0-Normal stomach

1-Petechial hemorrhage or pin point ulder

2-1 or 2 small ulcers

3 Many ulcers, a few large

4-Many ulcers, mainly large

Control animals treated with indomethacin but not test compoundconsistenly give scores of about 3.0. Control animals treated withneither indomethacin nor test compound gives scores of about 0.5-0.8.The results obtained in this assay with typical compounds of the presentinvention are set forth in Table A below. Compounds producing a loweringof the control score by 0.5 or more are considered to be active.

                  TABLE A                                                         ______________________________________                                                  Total Oral                                                                    dose; mg./kg.                                                                 of body  Score                                                      Compound    weight     Treated   Control                                      ______________________________________                                        9-oxo-15-hydroxy-                                                             17,20-methane-13-                                                                         12.5       1.8       2.8                                          trans-prostenoic                                                              acid                                                                          9-oxo-15-epi-                                                                 hydroxy-17,20-                                                                            25.0       1.7       3.0                                          methano-13-                                                                   trans-prostenoic -acid                                                        ______________________________________                                    

Bronchodilator activity was determined in guinea pigs againstbronchospasms elicited by intravenous injections of 5-hydroxytryptamine,histamine or acetylcholine by the Konzett procedure. [See J. Lulling, P.Lievens, F. El Sayed and J. Prignot, Arzneimittel-Forschung, 18, 995(1968).]

In the Table which follows bronchodilator activity for representativecompounds of this invention against one or more of three spasmogenicagents is expressed as an ED₅₀ determined from the results obtained withthree logarithemic cumulative intravenous doses.

                  TABLE B                                                         ______________________________________                                        Bronchodilator Activity (Konzett Assays)                                      ED.sub.50, mg./kg.                                                                        Spasmogenic Agent                                                               5-hydroxy-            acetyl                                    Compound      tryptamine histamine  choline                                   ______________________________________                                        9-oxo-15-hydroxy-                                                             17,20-methano-                                                                              6.3 × 10.sup.-3                                                                    1.4 × 10.sup.-3                                                                    3.2                                       13-trans-prosten-                                                             oic acid                                                                      9-oxo-15-epi- -hydroxy-17,20-                                                 methano-13-   3.2        206 × 10.sup.-3                                                                    3.2                                       trans-prostenoic                                                              acid                                                                          ______________________________________                                    

This invention will be described in greater detail in conjunction withthe following specific examples.

In the following examples, unless otherwise indicated, the productsobtained include all possible optical isomers.

EXAMPLES 1 Preparation of2-(6-carbethoxy-6-fluorohexyl)cyclopent-2-en-1-one

This cyclopentenone is prepared by the procedure described in BelgiumPat. No. 786,215 (Jan. 15, 1973) for the preparation of2-(6-carbethoxyoctyl)cyclopent-2-en-1-one by substituting diethylfluoromalonate for diethyl ethylmalonate.

EXAMPLE 2 Preparation of2-(6-carbethoxy-6-phenylhexyl)cyclopent-2-en-1-one

This cyclopentenone is prepared by the procedure described in BelgiumPat. No. 786,215 (Jan. 15, 1973) for the preparation of2-(6-carbethoxyoctyl)cyclopent-2-en-1-one by substituting diethylphenylmalonate for diethyl ethylmalonate.

EXAMPLE 3 Preparation of 2-(6-carbethoxy-heptyl)cyclopent-2-en-1-one

This cyclopentenone is prepared by the procedure described in BelgiumPat. No. 786,215 (Jan. 15, 1973) for the preparation of2-(6-carbethoxyoctyl)cyclopent-2-en-1-one by substituting diethylmethylmalonate for diethyl ethylmalonate.

EXAMPLE 4 Preparation of 2-(6-carbo-n-butoxyhexyl)cyclopent-2-en-1-one

A solution of 50 g. of 2-(6-carboxyhexyl)cyclopent-2-en-1-one [Bagli etal., Tetrahedron Letters, No. 5, 465 (1966)] in 1400 ml. of n-butanolcontaining 2.7 g. of p-toluenesulfonic acid monohydrate is allowed tostand at room temperature in a stoppered flask for about 24 hours. Thesolution is taken to dryness. The residue is taken up in ether and theethereal solution is washed several times with saline solution, driedwith anhydrous magnesium sulfate, and taken to dryness to afford thesubject butyl ester.

EXAMPLES 5-7

Treatment of 2-(6-carboxyhexyl)cyclopent-2-en-1-one by the procedure ofExample 5 with the appropriate alcohol affords the esters of thefollowing table.

                  TABLE 1                                                         ______________________________________                                        Ex-                                                                           ample     Alcohol     Product Ester                                           ______________________________________                                        5         isopropanol 2-(6-carboisopropoxyhexyl)-                                                   cyclopent-2-en-1-one                                    6         methanol    2-(6-carbomethoxyhexyl)-                                                      cyclopent-2-en-1-one                                    7         1-hydroxy-  2-(6-carbo-n-decyloxyhexyl)-                                      n-decane    cyclopent-2-en-1-one.                                   ______________________________________                                    

EXAMPLE 8 Preparation of 2-carbalkoxy(methyl/ethyl)-2-(2-methoxyethyl-cyclopentan-1-one

Treatment of 2-cyclopentenone carboxylate (mixed methyl and ethylesters) with 2-methoxyethyl bromide by the method of Example 1 ofBelgium Pat. No. 786,215 furnishes the subject compound as an oil, b.p.90° C. (0.1 mm).

EXAMPLE 9 Preparation of 2-(2-methoxyethyl)cyclopentan-1-one

Heating 8 g. of 2-carboalkoxy(methyl/ethyl)-2-(2-methoxyethyl)cyclopentan-1-one (Example 8) in 8 ml.of 20% aqueous hydrochloric acid at reflux for 3.5 hours and isolatingthe product by the method of Example 2 of Belgium Pat. No. 786,215furnishes the subject compound as an oil, b.p. 45°-50° C. (0.02 mm).

EXAMPLE 10 Preparation of 1-acetoxy-2-(2-methoxyethyl)cyclopent-1-ene

The subject compound is prepared from2-(2-methoxyethyl)cyclopentan-1-one (Example 9) and acetic anhydride bythe procedure

EXAMPLE 11 Preparation of 2-(2-hydroxyethyl)-cyclopent-2-en-1-one

The enol acetate of Example 10 is brominated and dehydrobrominated bythe method described in Example 28 of Belgium Pat. No. 786,215. Thecrude product is then dissolved in methylene chloride and is added at-78° C. to a methylene chloride solution containing about seven molarequivalents of boron tribromide. After one hour at -78° C. the solutionis allowed to warm to room temperature and is then kept at ambienttemperatures for a total of eighteen hours. The mixture is poured intowater and extracted with ether. The organic phase is washed withsaturated saline solution, then water and is dried. Evaporation ofsolvents leaves subject product, which is purified by distillation. Thecombined organic phases are washed with ice cold 5% sodium hydroxidesolution, ice cold 5% hydrochloric acid, and saturated sodium chloridesolution, dried with anhydrous magnesium sulfate and taken to dryness.Distillation gives a pale yellow oil; λ max 5.85μ (carbonyl group).

EXAMPLE 12 Preparation of 2-formylmethylcycopent-2-en-1-one

Chromium trioxide (0.6 mol) is added to a stirring solution of (1.2 mol)of anhydrous pyridine in 1500 ml. of anhydrous methylene chloride cooledin an ice bath. The deep red suspension is stirred for 15 minutes at 0°C. and 45 minutes at ambient temperature. A solution of 0.15 mol of2-(2-hydroxyethyl)-cyclopent-2-en-1-one (Example 11) in 50 ml. ofmethylene chloride is added, all at once, to the suspension. A blackterry deposit is formed immediately. After stirring the mixture for 25minutes at ambient temperature, the methylene chloride is decanted fromthe tarry precipitate which is then triturated several times with ether.

EXAMPLE 13 Preparation of2-(6-carboxy-2-cis-hexenyl)-cyclopent-2-en-1-one

A mixture of 0.194 g. (0.007952 mole) of sodium hydride (free of mineraloil) and 5.5 ml. of dimethylsulfoxide is heated to 70° C. until gasevolution ceases under a nitrogen atmosphere. The resulting solution iscooled below room temperature and treated with a solution of 1.400 g.(0.00316 mole) of 4-carboxybutyltriphenyl phosphonium bromide [E. J.Corey et al., J. Am. Chem. Soc., 91, 5675 (1969)] in 6 ml. ofdimethylsulfoxide. To the resulting red solution is added 0.00263 moleof 2-formylmethylcyclopent-2-en-1-one (Example 12) in 2 ml. ofdimethylsulfoxide and the mixture is stirred at room temperature for2.25 hours. The mixture is poured into ice water, sodium hydroxidesolution is added to pH 12, and the neutral materials are extracted withdiethyl ether. The basic phase is acidified with dilute hydrochloricacid and is extracted with diethyl ether. The organic phase is washedwith water and saturated brine, dried (Na₂ SO₄), and evaporated to asemicrystalline mass. The latter is triturated with hot hexane, thesolids are filtered off, and the filtrate is evaporated to yield thesubject product as an oil.

EXAMPLE 14 Preparation of2-(6-carbomethoxy-2-cis-hexenyl)-cyclopent-2-en-1-one

Treatment of 2-(6-carboxy-2-cis-hexenyl)-cyclopent-2-en-1-one (Example13) with diazomethane in the usual manner is productive of the subjectester.

EXAMPLE 15 Preparation of 1-oxa-2-hydroxy-bicyclo[3.3.0]oct-4-ene

A solution of 6.2 g. (50 mole) of the lactone ofcis-2-hydroxycyclopent-4-ene-1-acetic acid [P. A. Grieco, J. Org. Chem.,37, 2363 (1972)] in 350 ml. toluene (dried over molecular sieves) iscooled to -75° C. and treated dropwise under nitrogen with 84 ml. 0.89 Mdiisobutyl aluminum hydride (10.55 g., 74 mole) over a period of aboutone hour maintaining the temperature at -74+2° C. The resulting clearsolution is stirred at -75° C. for two hours and poured with stirringinto a mixture of 15 ml. of concentrated hydrochloric acid and 300 ml.of ice water. The mixture is stirred while warming to room temperature.The layers are separated and the aqueous layer is treated with salt andextracted with three small portions of ether. The combined organicportions are dried over sodium sulfate and evaporated at reducedpressure (75° C. water bath) to yield the product (homogeneous by thinlayer of chromatography) as a pale yellow mobile liquid.

EXAMPLE 16 Preparation of1-hydroxy-2-(6-carboxy-2-dix-hexenyl)cyclopent-3-ene

A solution of the sodium salt of dimethyl sulfoxide is prepared bystirring under nitrogen a mixture of 160 ml. dry dimethyl sulfoxide(dried over molecular sieves and a few pellets of calcium hydride) with6.0 g. (0.25 mole) of sodium hydride (prepared by making 10.5 g. of 57%sodium hydride dispersion in mineral oil with two 30 mll portions ofhexane.) The mixture is warmed with stirring at 75° C. (oil bath) for2.5 hours.

This solution is added during five minutes to a solution under nitrogenof 44 grams (0.1 mole) of 4-carboxybutyltriphenylphosphonium bromide(Example 18A) in 180 ml. of dry dimethyl sulfoxide. The resulting darkreddish brown solution is stirred for ten minutes, cooled to roomtemperature and treated with a solution of crude1-oxa-2-hydroxy-bicyclo[3.3.0]oct-4-ene (6.2 g., 50 mole) (Example 15)in 20 ml. of anhydrous dimethyl sulfoxide. The resulting solution isstirred 16 hours and then treated with 250 ml. ice water.

This brown solution is extracted with two portions of ether to removeneutral material then made strongly acidic with hydrochloric acid. Thesolution is extracted into four 100 ml. portions of methylene chloride.The combined methylene chloride extracts are mashed with water, thenextracted with four 100 ml. portions of 5% sodium bicarbonate. Thecombined aqueous extracts are mashed with methylene chloride and madeacidic to Congo Red with concentrated hydrochloric acid. The mixture isextracted with three 100 ml. portions of methylene chloride. The organicextracts are combined, dried over sodium sulfate and the solvent isevaporated at reduced pressure. The residue (an oily solid) is extractedseveral times with ether and the ethereal extracts are combined andevaporated at reduced pressure to yield the crude product as a dark oil.The product is purified by chromatograph 6 on silica gel, eluting in theether. The product is a colorless liquid.

EXAMPLE 17 Preparation of2-(6-carboxy-2-cis-hexenyl)cyclopent-3-en-1-one

A solution of 3.2 g. (0.5 mole) of1-hydroxy-2-(6-carboxy-2-cis-hexenyl)cyclopent-3-ene (Example 16) in 60ml. of reagent acetone is treated dropwise with a total of 6 ml. of 8 Nchromic acid in sulfuric acid at 0° C. The oxidation is rather slow. Theresulting mixture is dissolved in 200 ml. of water and the solution isextracted with six 50 ml. portions of ether. The combined etherealextracts are dried over sodium sulfate and the solvent is evaporated atreduced pressure to yield the product as a yellow oil.

EXAMPLE 18 Preparation of2-(6-carboxy-2-cis-hexenyl)cyclopent-2-en-1-one

A solution of 3 g. of crude2-(6-carboxy-2-cis-hexenyl)cyclopent-3-en-1-one (Example 17) in 100 ml.of 2% sodium hydroxide is stirred at 80° C. under nitrogen for 1.5hours. The cooled solution is acidified to Congo Red and extracted withether. The ethereal extracts are dried over sodium sulfate andevaporated at reduced pressure to afford the product.

EXAMPLE 18A Preparation of 4-carboxybutyltriphenylphosphonium bromide

A mixture of 103 g. of 5-bromoval eric acid and 152 g. oftriphenylphosphine in 400 ml. of acetonitrile is refluxed for 48 hours,cooled, diluted with 100 ml. of benzene and allowed to crystallize. Thecrystals are filtered, washed with benzene and ether, to yield colorlessmaterial, m.p. 207°-209° C.

EXAMPLES 18B-18D

Treatment of the indicated ω-bromoalkanoic acids of Table 3A below withtriphenylphosphine by the method described in Example 18A produces thephosphonium bromides of the table.

                  TABLE 2                                                         ______________________________________                                        Ex-     Starting (ω-bromo                                                                       Product                                               ample   alkanoic acid   phosphonium bromide                                   ______________________________________                                        18B     4-bromo-n-butyric                                                                             3-carboxypropyltri-                                           acid            phenylphosphonium                                     18C     6-bromo-n-hexanoic                                                                            5-carboxypentyltri-                                           acid            phenylphosphonium                                                             bromide                                               18D     7-bromo-n-hepta-                                                                              6-carboxyhexyltri-                                            noic acid       phenylphosphonium                                                             bromide                                               ______________________________________                                    

EXAMPLES 19-21

Treatment of 1-oxa-2-bicyclo[3.3.0]oct-4-ene by the procedure describedin Example 16 with the ylids derived from the phosphonium bromideslisted in Table 3 below furnishes the product 1-hydroxy-cyclopent-3-enesof the table.

                  TABLE 3                                                         ______________________________________                                                               Product                                                        Starting phos- 1-hydroxy-2-(ω-carboxy-                          Ex-     phonium bromide                                                                              2-cis-alkenyl)cyclopent-                               ample   of Example     3-enes                                                 ______________________________________                                        19      18B            1-hydroxy-2-(5-carboxy-                                                       2-cis-pentenyl)cyclo-                                                         pent-3-end                                             20      18C            1-hydroxy-2-(7-carboxy-                                                       2-cis-heptenyl)cyclo-                                                         pent-e-end                                             21      18D            1-hydroxy-2-(8-carboxy-                                                       2-cis-octenyl)cyclo-                                                          pent-3-ene                                             ______________________________________                                    

EXAMPLES 22-24

Oxidation of the 1-hydroxycyclopent-3-enes listed in Table 4 below bythe procedure described in Example 17 is productive of the productcyclopent-3-en-1-ones of the table.

                  TABLE 4                                                         ______________________________________                                                  Starting 1-   Product                                                         hydroxycyclo- 2-(ω-carboxy-2-cis-                             Ex-       pent-3-ene-of alkenyl)cyclopent-3-                                  ample     Example       en-1-one                                              ______________________________________                                        22        19            2-(5-carboxy-2-cis-                                                           pentenyl)cyclopent-3-                                                         en-1-one                                              23        20            2-(7-carboxy-2-cis-                                                           heptenyl)cyclopent-3-                                                         en-1-one                                              24        21            2-(8-carboxy-2-cis-                                                           octenyl)cyclopent-3-                                                          en-1-one                                              ______________________________________                                    

EXAMPLES 25-27

Base treatment according to the procedure described in Example 18 of thecyclopent-3-ene-1-ones listed in Table 5 below is productive of theproduct cyclopent-2-en-1-ones of the table.

                  TABLE 5                                                         ______________________________________                                                  Starting 2-(ω-                                                          carboxy-2-cis-                                                                              Product                                                         alkenyl)cyclo-                                                                              2-(ωcarboxy-2-cis-                              Ex-       pent-3-ene-1- alkenyl(cyclopent-                                    ample     one of Example                                                                              2-en-1-one                                            ______________________________________                                        25        22            2-(5-carboxy-2-cis-                                                           pentenyl)cyclopent-                                                           2-en-1-one                                            26        23            2-(7-carboxy-2-cis-                                                           heptenyl)cyclopent-                                                           2-en-1-one                                            27        24            2-(8-carboxy-2-cis-                                                           octenyl)cyclopent-                                                            2-en-1-one                                            ______________________________________                                    

EXAMPLES 28-30

Treatment of the listed 2-(ω-carboxy-2-cis-alkenyl)cyclopent-2-en-1-oneof Table 6 below with diazomethane in the usual manner is productive ofthe product methyl esters of the table.

                  TABLE 6                                                         ______________________________________                                                               Product                                                          Starting car-                                                                              2-(ω-carbomethoxy-2-cis-                         Ex-       boxylic acid alkenyl)cyclopent-2-en-                                ample     of Example   1-one                                                  ______________________________________                                        28        25           2-(5-carbomethoxy-2-cis-                                                      pentenyl)cyclopent-2-en-                                                      1-one                                                  29        26           2-(7-carbomethoxy-2-cis-                                                      heptenyl)cyclopent-2-en-                                                      1-one                                                  30        27           2-(8-carbomethoxy-2-cis-                                                      octenyl)cyclopent-2-en-                                                       1-one                                                  ______________________________________                                    

EXAMPLE 31 Preparation of cyclopentylacetyl chloride

To a solution of 50 g. of cyclopentaneacetic acid containing 2.9 ml. ofN,N-dimethylformamide is added dropwise with stirring, 51 g. of thionylchloride over a period of 15 minutes. After stirring for an additional60 minutes exces thionyl chloride is removed in vacuo and the residualoil is distilled to give 55.4 g. (97%) of product, b.p. 57°-58° C. (10mm.).

EXAMPLE 32 Preparation of 1-chloro-4-cyclopentyl-1-trans-buten-3-one

A three-necked flask fitted with a stirrer, a gas inlet tube and a gasoutlet tube protected with a calcium chloride tube is surrounded by anice-water bath. The system is flushed with acetylene for 3 minutes.Carbon tetrachloride (150 ml.) is added to the flask and acetylene isbubbled through at a fast rate for 3 minutes. Aluminum chloride (59 g.)is added and acetylene is bubbled through the mixture for 5 minutes. Thegas inlet tube is replaced by a dropping funnel protected by a calciumchloride drying tube. Cyclopentylacetyl chloride (55.4 g., Example 1) isadded to the reaction mixture stirring over a period of about 20minutes. The dropping funnel is replaced by the gas inlet tube and withstirring, acetylene gas is bubbled through at a rate in excess of thesaturation rate. After about 15 minutes the rate of absorption ofacetylene suddenly becomes very rapid, and the acetylene is passedthrough as rapidly as it is absorbed. The introduction of acetylene iscontinued for 45 minutes after the rapid absorption (which lasts about 1hour) has subsided.

The reaction mixture is poured with stirring into 430 g. of ice and 180ml. of saturated sodium chloride solution. The aqueous phase isextracted three times with ether. The combined extracts are dried withanhydrous magnesium sulfate and evaporated to dryness in vacuo. Afteraddition of 1.5 g. of hydroquinone the residual oil is distilled to give57 g. (80%) of oil, b.p. 67°-69° C. (0.14 mm.).

EXAMPLE 33 Preparation of 4-cyclopentyl-1-iodo-1-trans-buten-3-one

A solution of 57 g. of 1-chloro-4-cyclopentyl-trans-buten-3-one (Example32) in 360 ml. of acetone containing 55 g. of sodium iodide is stirredat the reflux temperature for 18 hours. The resulting mixture is cooled,filtered and and the water liquor is taken to dryness. The residual oilis dissolved in ether washed successively with water, dilute sodiumthiosulfate solution, and saturated sodium chloride solution, dried withanhydrous magesium sulfate and taken to dryness to give 87 g. (99%) oforange oil. Vapor phase chromatography shows one peak.

EXAMPLE 34 Preparation of 4-cyclopentyl-1-iodo-1-trans-buten-3-ol

To a solution of 7.1 g. of sodium borohydride in 60 ml. of absolutealcohol, stirred in an ice bath under nitrogen atmosphere, is addeddropwise, over a period of about 2 hours, a solution containing 7 g. of4-cyclopentyl-1-iodo-1-trans-buten-3-one (Example 33) in 160 ml. ofabsolute alcohol. The temperature is maintained at 5°-10° C. Thesolution is poured into 850 ml. of iced water and the resulting mixtureis extracted three times with ether. The combined extracts are washedwith dilute sodium bisulfite solution, saturated sodium chloridesolution, dried with anhydrous magnesium sulfate and taken to dryness togive 81 g. of yellow oil. Column chromatography on a column of 1 kg. ofsilica gel using benzene gives 75 g. (88%) of oily product.

EXAMPLES 35-58

Treatment of the listed carboxylic acids in Table 1 below with thionylchloride by the procedure disclosed in Example 31 followed by treatmentof the resulting acid chloride with acetylene by the procedure describedin Example 32, and thence by treatment of the resulting1-chloro-1-trans-alkene-3-one with sodium iodide by the proceduredescribed in Example 33, and then by treatment of the resulting1-iodo-1-trans-alkene-3-one with sodium borohydride by the proceduredescribed in Example 34 is productive of the product3-hydroxy-1-iodo-1-trans-alkenes of the table.

                  TABLE 1                                                         ______________________________________                                                               Product 3-hydroxy-                                     Ex-     Starting       1-iodo-1-                                              ample   Carboxylic acid                                                                              trans-alkene                                           ______________________________________                                        35      Cyclobutylacetic                                                                             4-Cyclobutyl-3-hydroxy-                                        acid.sup.1     1-iodo-1-trans-butene                                  36      3-Cyclopentyl- 5-Cyclopentyl-3-hydroxy-                                       propionic acid 1-iodo-1-trans-pentene                                 37      4-Cyclopentyl- 6-Cyclopentyl-3-hydroxy-                                       butyric acid.sup.2                                                                           1-iodo-1-trans-hexene                                  38      5-Cyclopentyl- 7-Cyclopentyl-3-hydroxy-                                       pentanoic acid.sup.2                                                                         1-iodo-1-trans-heptene                                 39      6-Cyclopentyl- 8-Cyclopentyl-3-hydroxy-                                       hexanoic acid.sup.2                                                                          1-iodo-1-trans-octene                                  40      2-Methyl-3-cyclo-                                                                            5-Cyclopentyl-4-methyl-                                        pentylpropanoic                                                                              3-hydroxy-1-iodo-1-                                            acid.sup.3     trans-pentene                                          41      2-Ethyl-4-cyclo-                                                                             6-cyclopentyl-4-ethyl-                                         pentylbutyric  3-hydroxy-1-iodo-1-                                            acid.sup.4     trans-hexene                                           42      (2-trans-methyl-                                                                             4-(2-trans-methyl-                                             cyclopentyl)-  cyclopentyl)-3-hydroxy-                                        acetic acid.sup.5                                                                            1-iodo-1-trans-butene                                  43      4-(2-trans-    6-(2-trans-methylcyclo-                                        methylcyclo-   pentyl)-3-hydroxy-1-                                           pentyl)butyric iodo-1-trans-hexene                                            acid.sup.5                                                            44      Cyclohexylacetic                                                                             4-Cyclohexyl-3-hydroxy-                                        acid           1-iodo-1-trans-1-trans-                                                       butene                                                 45      3-Cyclohexyl-  5-cyclohexyl-3-hydroxy-                                        propionic acid 1-iodo-1-trans-pentene                                 46      4-Cyclohexyl-  6-cyclohexyl-3-hydroxy-                                        butyric acid.sup.6                                                                           1-iodo-1-trans-hexene                                  47      Cycloheptyl-   4-Cycloheptyl-3-hydroxy-                                       acetic acid.sup.7                                                                            1-iodo-1-trans-butene                                  48      (4-methylcyclo-                                                                              4-(4-methylcycloheptyl)-                                       heptyl)acetic  3-hydroxy-1-iodo-1-                                            acid.sup.8     trans-butene                                           49      Cyclooctylacetic                                                                             4-Cyclooctyl-3-hydroxy-                                        acid.sup.8,9   1-iodo-1-trans-butene                                  50      (4-methylcyclo-                                                                              4-(4-methylcyclohexyl)-                                        hexyl)acetic   3-hydroxy-1-iodo-1-                                            acid.sup.10    trans-butene                                           51      (3-methylcyclo-                                                                              4-(3-methylcyclohexyl)-                                        hexyl)acetic   3-hydroxy-1-iodo-1-                                            acid.sup.11    trans-butene                                           52      3-Cycloheptane 3-Cycloheptyl-3-hydroxy-                                       carboxylic acid                                                                              1-iodo-1-trans-propene                                 53      Cyclopentane-  3-Cyclopentyl-3-hydroxy-                                       carboxylic acid                                                                              1-iodo-1-trans-                                                               propene                                                54      Trans-2-methyl-                                                                              3-(Trans-2-methylcyclo-                                        cyclopentane   pentyl-3-hydroxy-1-                                            carboxylic acid.sup.12                                                                       iodo-1-trans-propene                                   55      all-trans-2,3- 3-(all-trans-2,3-di-                                           dimethylcyclo- methylcyclopentyl)-1-                                          pentane car-   iodo-1-trans-propene                                           boxylic acid.sup.13                                                   56      Cyclohexane car-                                                                             3-Cyclohexyl-3-hydroxy-                                        boxylic acid   1-iodo-1-trans-propene                                 57      Trans-4-methyl-                                                                              3-(trans-4-methylcyclo-                                        cyclohexane    hexyl)-3-hydroxy-1-iodo-                                       carboxylic acid                                                                              1-trans-propene                                        58      Cyclooctane, car-                                                                            3-Cyclooctyl-3-hydroxy-                                        boxylic acid.sup.14                                                                          1-iodo-1-trans-propene                                 ______________________________________                                         .sup.1 C. G. Overberger et al., J. Polymer Sci., Pt. A, 2, 755(1964.          .sup.2 M. I. Goryaev et al., Chem. Abs., 69, 1742, No. 186462 (1968).         .sup.3 C. D. Nenitzescu and G. G. Vantu, Bull. Soc. Chim.                     .sup.4 France [5]. 2, 2209 (1935). 4G. R. Yohe and R. Adams, J. Amer.         Chem. Soc., 50, 1503 (1928).                                                  .sup.5 W. Herz, J. Org. Chem., 20, 1062 (1955).                               .sup.6 G. S. Hiers and R. Adams, J. Amer. Chem. Soc., 48, 2385 (1926).        .sup.7 E. E. Royals and A. N. Neal, J. Org. Chem., 21, 1448 (1956).           .sup.8 F. F. Blicke and W. K. Johnson, J. Am. Pharm. Assoc. Sci. Ed., 45,     443 (1956).                                                                   .sup.9 L. Ruzicka and H. A. Bockenoogen, Helv. Chim. Acta, 14, 1319           (1931).                                                                       .sup.10 A. W. Burgstahler and I. C. Nordin, J. Amer. Chem. Soc., 83, 198      (1961).                                                                       .sup.11 J. von Braun and W. Teuffert, Ber., 58B, 2210 (1925).                 .sup.12 M. Julia and F. LeGoffie, Bull. Soc. Chim. Fr., 1550 (1965).          .sup.13 V. N. Ipatieff et al., J. Amer. Chem. Soc., 75, 6222 (1953).          .sup.14 A. T. Blomquist and F. W. Sehlaefe, J. Amer. Chem. Soc., 83, 4547     (1961).                                                                  

EXAMPLE 59 Preparation of4-cyclopentyl-1-iodo-3-triphenylmethoxy-1-trans-butene

A mixture of 21.4 g. of 4-cyclopentyl-1-iodo-trans-buten-3-ol (Example34) in 170 ml. of dry pyridine containing 31 g. of triphenylmethylbromide is heated on the steam bath for 2 hours. The dark mixture ispoured into 850 ml. of iced water and the resulting solution isextracted three times with ether. The combind extracts are washed withice cold 2% hydrochloric acid until the washings are acidic, saturatedsodium chloride solution, dried with anhydrous magnesium sulfate andtaken to dryness. Trituration of the residue followed by filtrationremoves triphenylcarbinol. The mother liquor is taken to dryness and theresidual syrup is chromatographed on 400 g. of florisil using hexanegives 32 g. (78%) of syrup which solidifies on standing.Recrystallization from hexane affors white crystals, m.p. 87°-88° C.

EXAMPLE 60 Preparation of4-cyclopentyl-1-iodo-3-(p-methoxyphenyldiphenyl)methoxy-1-trans-butene

A solution of 20 g. of 4-cyclopentyl-1-iodo-1-trans-butene-3-ol (Example34) and 25 g. of p-anisylchlorodiphenylmethane in 170 ml. of drypyridine is kept at 60° C. for 18 hours, then at 70° C. for 3 hours. Thecooled solution is poured into 850 ml. of iced water. The resultingsolution is partitioned between ether and water. The ether layer iswashed with water, dried with anhydrous magnesium sulfate and taken todryness. Further evaporation with toluene removes residual pyridine. Theresulting oil is chromatographed on 300 g. of fluorisil with hexanes togive 22.3 g. of product. The material is homogeneous according to thinlayer chromatography.

EXAMPLES 61-84

Treatment of the listed 3-hydroxy-1-iodo-trans-1-alkenes of Table 2below with triphenylmethylbromide by the procedure described in Example59 above is productive of the product3-triphenylmethoxy-1-iodo-trans-1-alkenes of the table.

                  TABLE 2                                                         ______________________________________                                                  Starting                                                                      3-hydroxy-                                                                    1-iodo-1-    Product                                                Ex-       trans-alkene 3-triphenylmethoxy-                                    ample     of Example   1-iodo-trans-1-alkene                                  ______________________________________                                        61        35           4-Cyclobutyl-3-tri-                                                           phenylmethoxy-1-iodo-                                                         1-trans-butene                                         62        36           5-Cyclopentyl-3-tri-                                                          phenylmethoxy-1-iodo-                                                         1-trans-pentene                                        63        37           6-Cyclopentyl-3-tri-                                                          phenylmethoxy-1-iodo-                                                         1-trans-hexene                                         64        38           7-Cyclopentyl-3-tri-                                                          phenylmethoxy-1-iodo-                                                         1-trans-heptene                                        65        39           8-Cyclopentyl-3-tri-                                                          Phenylmethoxy-1-iodo-                                                         1-trans-octene                                         66        40           5-Cyclopentyl-4-meth-                                                         yl-3-triphenylmethoxy-                                                        1-iodo-1-trans-pentene                                 67        41           6-Cyclopentyl-4-ethyl-                                                        3-triphenylmethoxy-1-                                                         iodo-1-trans-hexene                                    68        42           4-(2-trans-methylcyclo-                                                       pentyl)-3-triphenyl-                                                          methoxy-1-iodo-1-trans-                                                       butene                                                 69        43           6-(2-trans-methylcyclo-                                                       pentyl)-3-triphenyl-                                                          methoxy-1-iodo-1-trans-                                                       hexene                                                 70        44           4-Cyclohexyl-3-tri-                                                           phenylmethoxy-1-iodo-                                                         1-trans-butene                                         71        45           5-Cyclohexyl-3-tri-                                                           phenylmethoxy-1-iodo-                                                         1-trans-pentene                                        72        46           6-Cyclohexyl-3-tri-                                                           phenylmethoxy-1-iodo-                                                         1-trans-hexene                                         73        47           4-Cycloheptyl-3-tri-                                                          phenylmethoxy-1-iodo-                                                         1-trans-butene                                         74        48           4-(4-methylcycloheptyl)-                                                      3-triphenylmethoxy-1-                                                         iodo-1-trans-butene                                    75        49           4-Cyclooctyl-3-triphen-                                                       ylmethoxy-1-iodo-1-                                                           trans-butene                                           76        50           4-(4-methylcyclohexyl)-                                                       3-triphenylmethoxy-1-                                                         iodo-1-trans-butene                                    77        51           4-(3-methylcyclohexyl)-                                                       3-triphenylmethoxy-                                                           1-iodo-1-trans-butene                                  78        52           3-Cycloheptyl-3-tri-                                                          phenylmethoxy-1-iodo-                                                         1-trans-propene                                        79        53           3-Cyclopentyl-3-tri-                                                          phenylmethoxy-1-iodo-                                                         1-trans-propene                                        80        54           3-(trans-2-methylcyclo-                                                       pentyl)-3-triphenyl-                                                          methoxy-1-iodo-1-trans-                                                       propene                                                81        55           3-(all-trans-2,3-di-                                                          methylcyclopentyl)-3-                                                         triphenylmethoxy-1-                                                           iodo-1-trans-propene                                   82        56           3-Cyclohexyl-3-triphen-                                                       ylmethoxy-1-iodo-1-                                                           trans-propene                                          83        57           3-(trans-4-methylcyclo-                                                       hexyl)-3-triphenyl-                                                           methoxy-1-iodo-1-trans-                                                       propene                                                84        58           3-Cyclooctyl-3-tri-                                                           phenylmethoxy-1-iodo-1-                                                       trans-propene                                          ______________________________________                                    

EXAMPLE 84A Preparation of 1,1-dimethyl-cis-3,4-methylenehexane(cis-1-ethyl-2(2,2-dimethoxyethyl)cyclopropane

To an ethereal suspension of zinc-silver couple, prepared according tothe procedure of J. M. Denis, G. Girard, and J. M. Conia (Synthesis,1972, 549) from 0.400 g. of silver acetate, 400 ml. of acetic acid, 68g. of granular zinc, silver wool, and 600 ml. of ether is added dropwise136 g. of diiodomethane at a rate to maintain a gentle reflux. Themixture is then stirred at room temperature for 1 hour and to it is thenadded 57.7 g. of 1,1-dimethoxy-cis-3-hexane. [(M. Winter, HelveticaChimica Acta, 46, 1972 (1963)] over a period of 20 minutes and themixture is refluxed for 5 hours. The mixture is cooled to 0° C., 600 ml.of ether is added followed by 50.5 g. of pyridine dropwise over a periodof 1 hour. The resulting precipitate is filtered and washed with ether.The filtrate and washings are combined and evaporated and the residue isfractionally distilled at 12 torr to yield the title compound as acolorless oil.

EXAMPLE 84B Preparation of cis-3,4-methylene-1-hexanol

To a vigorously stirred solution of 31.6 g. of1,1-dimethoxy-cis-3,4-methylene-hexane (Example 84A), 75 mg. ofhydroquinone, 6 g. of oxalic acid in 150 ml. of acetone heated at 45° C.under an inert atmosphere is added 700 ml. of water over a period of 0.5hours. The mixture is cooled and extracted well with ether. The organicphase is separated, washed with saturated sodium bicarbonate solutionand saturated brine, dried (Na₂ SO₄) and evaporated. The residue isdistilled at 30 torr. to yield the title compound.

EXAMPLE 85 Preparation of cis-5,6-methylene-1-octyn-3-ol

To a solution of 15.2 g. (0.165 mole) of lithiumacetylide-ethylenediamine complex in 100 ml. of dry dimethylsulfoxide isadded 16.8 g. (0.150 mole) of cis-3,4-methylene-1-hexanol (Example 84B)in 25 ml. of dimethylsulfoxide at a rate to maintain a temperature of25° C. (cooling). The mixture is then maintained at 25° C. for 2 hoursand is poured onto ice and excess hydrochloric acid. The mixture isextracted with ether and the organic phase is washed with water andsaturated brine, dried (Na₂ SO₄), and evaporated to an oil. Distillationin vacuo yields the title compound as a colorless oil.

EXAMPLE 85A Preparation of 3-triphenylmethoxy-cis-5,6-methylene-1-octyne

A mixture of 13.8 g. of cis-5,6-methylene-1-octyn-3-ol (Example 85) and33.0 g. of triphenylmethyl bromide in 100 ml. of pyridine is heated to100° C. for 1.5 hours under an inert atmosphere. The mixture is cooledand filtered. The filtrate is partitioned between ice water and ether.The organic phase is washed with cold dilute hydrochloric acid,saturated sodium bicarbonate solution, and saturated brine, dried(NaSO₄), and evaporated to an oil. The latter is dissolved in hexane andpassed through 400 g. of Florisil® to yield after evaporation the titlecompound as a colorless oil.

EXAMPLE 86 Preparation of1-iodo-3-triphenylmethoxy-cis-5,6-methylene-trans-1-octene

To 160 ml. of a 0.50 M solution of disiamylborane in diglyme cooled to0° C. under an inert atmosphere is added 28.6 g. (0.075 mole)3-triphenylmethoxy-cis-5,6-methylene-1-octyne (Example 85A). The mixtureis allowed to come to room temperature and is stirred at ambienttemperature for 3 hours. The solution is cooled to 0° C. and 16.9 g.(0.225 mole) of triethylamine oxide is added portionwise such that thetemperature is maintained at 0°-5° C. The mixture is stirred at 0° C.for 1 hour and is then poured into 300 ml. of 1 N sodium hydroxidefollowed immediately by a solution of 57 g. (0.225 mole) of iodine in150 ml. of tetrahydrofuran. The mixture is stirred at ambienttemperatures of 0.5 hour and poured into 1000 ml. of water. The mixtureis decolorized by addition of sodium thiosulfate solution and isextracted into ether. The organic phase is washed with water and thesolvent is removed in vacuo. The residue is purified by dry-columnchromatography upon 1.5 kg. of alumina using hexane as eluent The titlecompound is obtained as an oil.

EXAMPLES 87-93B

Treatment of the carboxaldehydes listed in Table 3 below with lithiumacetylide by the procedure described in Example 85 followed by treatmentof the resulting 3-hydroxy-1-alkyne with triphenylmethyl bromide by theprocedure of Example 85A furnishes the product3-triphenylmethoxy-1-alkynes of the table.

                  TABLE 3                                                         ______________________________________                                        Ex-     Starting carbox-                                                                             Product 3-triphenyl-                                   ample   aldehyde       methoxy-1-alkynes-                                     87      (2-cyclopenten-                                                                              4-(2-cyclopentenyl)-3-                                         yl)acetaldehyde.sup.1                                                                        triphenylmethoxy-1-                                                           butyne                                                 88      (2-cyclohexenyl)-                                                                            4-(2-cyclohexenyl-3-                                           acetaldehyde.sup.1                                                                           triphenylmethoxy-1-                                                           butyne                                                 89      (3-cyclohexenyl)-                                                                            4-(3-cyclohexenyl)-3-                                          acetaldehyde.sup.1                                                                           triphenylmethoxy-1-                                                           butyne                                                 90      1-methyl-1-form-                                                                             1-methyl-1-(3-tri-                                             ylmethylcyclo- phenylmethoxy-1-butyn-                                         hexane         yl-4)cyclohexane                                       91      adamantane-1-car-                                                                            3-(1-adamantyl)-3-tri-                                         boxaldehyde    phenylmethoxy-1-propyne                                92      2-cyclohexene  3-(2-cyclohexenyl)-3-                                          carboxaldehyde triphenylmethoxy-1-                                                           propyne                                                93      3-cyclohexene  3-(3-cyclohexenyl)-3-                                          carboxaldehyde triphenylmethoxy-1-                                                           propyne                                                  93A   adamantane-2-  3-(2-adamantyl)-3-tri-                                         carboxaldehyde.sup.2                                                                         phenylmethoxy-1-propyne                                  93B   (adamantyl-1)- 4-(1-adamantyl)-3-tri-                                         actaldehyde                                                           phenylmethoxy                                                                 ______________________________________                                         References (Table 3)?                                                         .sup.1 C. W. Whitehead et al., J. Org. Chem., 26, 2814 (1961).                .sup.2 A. H. Alberts, H. Wynberg and J. Strating, Synthetic                   Communications, 2, 79 (1972).                                            

EXAMPLES 94-100B

Treatment of the 3-triphenylmethoxy-1-alkynes listed in Table 4 belowwith disiamylborane, trimethylamine oxide; iodine and aqueous sodiumhydroxide by the procedure described in Example 86 furnishes the product3-triphenylmethoxy-1-iodo-1-trans-alkenes of the table.

                  Table 4                                                         ______________________________________                                                Starting 3-tri-                                                               phenylmethoxy- Product 3-triphenyl-                                   Ex-     1-alkynes of   methoxy-1-iodo-1-trans-                                ample   Example        alkene                                                 ______________________________________                                        94      87             4-(2-cyclopentenyl)-3-                                                        triphenylmethoxy-1-                                                           iodo-1-trans-butene                                    95      88             4-(2-cyclohexenyl)-3-                                                         triphenylmethoxy-1-iodo                                                       1-trans-butene                                         96      89             4-(3-cyclohexenyl)-3-                                                         triphenylmethoxy-1-                                                           iodo-1-trans-butene                                    97      90             1-methyl-1-(3-triphen-                                                        ylmethoxy-1-iodo-trans-                                                       1-butenyl-4)cyclo-                                                            hexane                                                 98      91             3-(1-adamantyl)-3-tri-                                                        phenylmethoxy-1-iodo-                                                         1-trans-propene                                        99      92             3-(2-cyclohexenyl)-3-                                                         triphenylmethoxy-1-                                                           iodo-1-trans-propene                                   100     93             3-(3-cyclohexenyl)-3-                                                         triphenylmethoxy-1-                                                           iodo-1-trans-propene                                   100A    93A            3-(2-adamantyl)-3-tri-                                                        phenylmethoxy-1-iodo-                                                         1-trans-propene                                        100B    93B            4-(1-adamantyl)-3-tri-                                                        phenylmethoxy-1-iodo-                                                         1-trans-butene                                         ______________________________________                                    

EXAMPLE 101 Preparation of methyl9-oxo-15-hydroxy-17,20-methano-13-trans-prostenoate(11-deoxy-17,20-methanoprostaglandin-E₁methylester)

To a solution of 6.35 g. (12.5 mmoles) of4-cyclopentyl-1-iodo-3-triphenylmethoxy-1-trans-butene (Example 59) in15 ml. of dry toluene, cooled to -78° C. in a nitrogen atmosphere, isadded dropwise within 10 minutes, 5.4 ml. (12.5 mmoles) of a 2.34 molarsolution of n-butyllithium in hexane. The solution is allowed to warm to-40° C. and is maintained at that temperature for 1 hour. The resultingsolution containing(3-triphenylmethoxy-4-cyclopentyl-1-trans-butenyl)lithium is cooled to-78° C. and there is added dropwise 5.15 ml. (12.5 mmoles) of a 2.44molar solution of trimethylaluminum in heptane. The resulting solutioncontaining lithio(3-triphenylmethoxy-4-cyclopentyl-1-trans-butenyl)trimethyl alanate isallowed to warm to -10° C., cooled to -35° C. and there is addeddropwise 2.24 g. (10 mmoles) of 2-(6-carbomethoxyhexyl)-2-cyclopentenone(Example 6) in 10 ml. of ether. The 2-phase mixture is then allowed towarm to ambient temperature and is stirred for 18 hours.

The resulting single phase solution is poured cautiously into ice andexcess dilute aqueous hydrochloric acid. Ether is added and the organicphase is separated, washed successively with water and saturated sodiumchloride solution, dried with anhydrous magnesium sulfate and evaporatedto give 8.35 g. methyl9-oxo-15-triphenylmethoxy-17,20-methano-13-trans-prostenoate as an oil.

The oil is heated under nitrogen atmosphere in 100 ml. of 80% aqueousacetic acid at 80°-85° C. for 1 hour. The resulting solution is take todryness then evaporated two times with toluene. The resulting oil istriturated with 15 ml. of hexane and filtered to removetriphenylcarbinol (2.5 g., m.p. 156°-158° C.). Evaporation of the motherliquor gives 4.8 g. of viscous oil. The oil, dissolved in 2 ml. ofmethylene chloride, is applied to a dry column (nylon tube, 17/8"flat×36") containing 360 g. of silica gel. The column (30" long) isdeveloped with benzene-ethyl acetate (4:1). The first and last 3" of thecolumn are discarded; the remainder of the column being divided into11/2" segments. Each of the sixteen segments is triturated with ether,filtered and taken to dryness Segments 1 and 2 give no material.Segments 3, 4 and 5 afford. 512.7 mg. of methyl9-oxo-15-hydroxy-17,20-methano-13-trans-prostenoate(11-deoxy-17,20-methano-prostaglandin-E₁methyl ester); λmax 2.86 (OH), 5.75 (C═O), and 10.25μ (trans--CH═CH--);thin layer chromatography shows one spot, Rf 0.189. Segments 6 and 7 arecombined to give 622 mg. of oil which after partition chromatographyaffords 193 mg. of methyl 9-oxo-15-epi-hydroxy-17,20-methano-13-trans-prostenoate.(15-epi-11-deoxy-17,20-methyleneprostaglandin-E₁ methyl ester); λmax2.86 (OH), 5.75 (C═O), and 10.25μ (trans--CH═CH--); thin layerchromatography shows one spot, Rf 0.266. There is also obtained anadditional 237 mg. of 11-deoxy-17,20-methanolprostaglandin-E₁ methylester identical in all respects to the material found in segments 3, 4and 5 above. Segments 8 and 9 are combined to give 850.7 mg. of oilwhich when further purified by partition chromatography gives 601 mg. of15-epi-11-deoxy-17,20-methanoprostaglandin-E₁, methyl ester identicalwith the material obtained above.

EXAMPLE 102 Preparation of9-oxo-15-hydroxy-17,20-methano-13-trans-prostenoicacid(11-deoxy-17,20-methanoprostaglandin-E₁)

A suspension of 512.7 mg. of 11-deoxy-17,20-methano prostaglandin-E₁methyl ester (Example 101) in 10 ml. of methanol-water (1:1) containing200 mg. of potassium hydroxide is stirred under nitrogen atmosphere at50° C. for 1 hour. The resulting solution is then stirred at ambienttemperature for 18 hours. The solution is cooled in an ice-bath,acidified with 1 N hydrochloric acid and extracted several times withether. The combined extracts are washed with saturated sodium chloridesolution, dried with anhydrous magnesium sulfate and taken to dryness togive 481 mg. (98%) of syrup which cyrstallizes on standing.

EXAMPLE 103 Preparation of9-oxo-15-epi-hydroxy-17,20-methano-13-trans-prostenoicacid(15-epi-11-deoxy-17,20-methanoprostaglandin-E₁)

A suspension of 767 mg. of 15-epi-11-deoxy-17,20-methanoprostaglandin E₁(Example 101) in 16 ml. of methanol-water (1:1) containing 300 mg. ofpotassium hydroxide is treated in the manner described in Example 102 togive 690 mg. (94%) of syrupy product which cyrstallizes on standing.

EXAMPLES 104-134

Treatment of the 3-triphenylmethoxy-1-iodo-1-trans-alkenes listed inTable 5 below with butyl lithium by procedure described in Example 101above is productive of the 3-triphenylmethoxy 1-trans-alkenyl lithiumderivatives of the table.

                  Table 5                                                         ______________________________________                                                Starting                                                                      3-triphenyl-                                                                  methoxy-1-iodo-                                                                              Product 3-                                             Ex-     trans-1-alkene triphenylmethoxy-1-                                    ample   of Example     trans-alkenyl lithium                                  ______________________________________                                        104     61             4-Cyclobutyl 3-tri-                                                           phenylmethoxy-1-trans-                                                        butenyl lithium                                        105     62             5-Cyclopentyl-3-tri-                                                          phenylmethoxy-1-trans-                                                        pentenyl lithium                                       106     63             6-Cyclopentyl-3-tri-                                                          phenylmethoxy-1-trans-                                                        hexenyl lithium                                        107     64             7-Cyclopentyl-3-tri-                                                          phenylmethoxy-1-trans-                                                        heptenyl lithium                                       108     65             8-Cyclopentyl-3-tri-                                                          phenylmethoxy-1-trans-                                                        octenyl lithium                                        109     66             5-cyclopentyl-4-methyl-                                                       3-triphenylmethoxy-1-                                                         trans-pentenyl lithium                                 110     67             6-cyclopentyl-4-ethyl-                                                        3-triphenylmethoxy-1-                                                         trans-hexenyl lithium                                  111     68             4-(2-trans-methyl                                                             cyclopentyl)-3-tri-                                                           phenylmethoxy-1-trans-                                                        butenyl lithium                                        112     69             6-(2-trans-methylcyclo-                                                       pentyl)-3-triphenyl-                                                          methoxy-1-trans-hexenyl                                                       lithium                                                113     70             4-Cyclohexyl-3-tri-                                                           phenylmethoxy-1-trans-                                                        butenyl lithium                                        114     71             5-Cyclohexyl-3-tri-                                                           phenylmethoxy-1-trans-                                                        pentenyl lithium                                       115     72             6-Cyclohexyl-3-tri-                                                           phenylmethoxy-1-trans-                                                        hexenyl lithium                                        116     73             4-Cycloheptyl-3-tri-                                                          phenylmethoxy-1-trans-                                                        butenyl lithium                                        117     74             4-(4-methylcycloheptyl)-                                                      3-triphenylmethoxy-1-                                                         trans-butenyl lithium                                  118     75             4-Cyclooctyl-3-tri-                                                           phenylmethoxy-1-trans-                                                        butenyl lithium                                        119     76             4-(4-methylcyclohexyl)-                                                       3-triphenylmethoxy-1-                                                         trans-butenyl lithium                                  120     77             4-(3-methylcyclohexyl)-                                                       3-triphenylmethoxy-1-                                                         trans-butenyl lithium                                  121     93B            4-(1-adamantyl)-3-tri-                                                        phenylmethoxy-1-trans-                                                        butenyl lithium                                        122     79             3-Cyclopentyl-3-tri-                                                          phenylmethoxy-1-trans-                                                        propenyl lithium                                       123     80             3-(trans-2-methyl-                                                            cyclopentyl)-3-tri-                                                           phenylmethoxy-1- trans-                                                       propenyl lithium                                       124     81             3-(all trans-2,3-di-                                                          methylcyclopentyl)-1-                                                         trans-propenyl lithium                                 125     82             3-Cyclohexyl-3-triphen-                                                       ylmethoxy-1-trans-                                                            propenyl lithium                                       126     83             3-(trans-4-methylcyclo-                                                       hexyl)-3-triphenyl-                                                           methoxy-1-trans-prop-                                                         enyl lithium                                           127     84             3-Cyclooctyl-3-tri-                                                           phenylmethoxy-1-trans-                                                        propenyl lithium                                       128     87             4-(2-cyclopenenyl)-3-                                                         triphenylmethoxy-1-                                                           trans-butenyl lithium                                  129     88             4-(2-cyclohexenyl)-3-                                                         triphenylmethoxy-1-                                                           trans-butenyl lithium                                  130     89             4-(3-cyclohexenyl)-3-                                                         triphenylmethoxy-1-                                                           trans-butenyl lithium                                  131     90             1-Methyl-1-(3-triphen-                                                        ylmethoxy-trans-1-                                                            butenyl-4)-cyclohexyl                                                         lithium                                                132     91             3-(1-adamantyl)-3-                                                            triphenylmethoxy-1-                                                           trans-propenyl lithium                                 133     92             3-(2-cyclohexenyl)-3-                                                         triphenylmethoxy-1-                                                           trans-propenyl lithium                                 134     93             3-(3-cyclohexenyl)-3-                                                         triphenylmethoxy-1-                                                           trans-propenyl lithium                                  134A   93A            3-(2-adamantyl)-3-                                                            triphenylmethoxy-1-                                                           trans-propenyl lithium                                  134B   78             3-Cycloheptyl-3-tri-                                                          phenylmethoxy-1-trans-                                                        propenyl lithium                                       ______________________________________                                    

EXAMPLES 135-165

Treatment of the 3-triphenylmethoxy-1-trans-alkenyl lithium derivativelisted in Table 6 below with trimethyl aluminum by the proceduredescribed in Example 101 above furnishes of the product lithio(3-triphenylmethoxy-1-trans-alkenyl)trimethyl alanates of the table.

                  Table 6                                                         ______________________________________                                                Starting                                                                      3-triphenyl-   Product lithio-                                                methoxy-1-trans-                                                                             (triphenylmethoxy-                                     Ex-     alkenyl lithium                                                                              1-trans-alkenyl)-                                      ample   of Example     trimethyl alanate                                      ______________________________________                                        135     104            lithio(4-cyclobutyl-                                                          3-triphenylmethoxy-1-                                                         trans-butenyl)trimethyl                                                       alanate                                                136     105            lithio (5-cyclopentyl-                                                        3-triphenylmethoxy-1-                                                         trans-pentenyl)tri-                                                           methyl alanate                                         137     106            lithio(6-cyclopentyl-3-                                                       triphenylmethoxy-1-                                                           trans-hexenyl)trimethyl                                                       alanate                                                138     107            lithio(7-cyclopentyl-3-                                                       triphenylmethoxy-1-                                                           trans-heptenyl)trimethyl                                                      alanate                                                139     108            lithio(8-cyclopentyl-                                                         3-triphenylmethoxy-1-                                                         trans-octenyl)trimethyl                                                       alanate                                                140     109            lithio(5-cyclopentyl-                                                         4-methyl-3-triphenyl-                                                         methoxy-1-trans-                                                              pentenyl)trimethyl                                                            alanate                                                141     110            lithio(6-cyclopentyl-                                                         4-ethyl-3-triphenyl-                                                          methoxy-1-trans-hexenyl)                                                      trimethyl alanate                                      142     111            lithio[4-(2-trans-                                                            methylcyclopentyl)-                                                           3-triphenylmethoxy-1-                                                         trans-butenyl)tri-                                                            methyl alanate                                         143     112            lithio[6-1-trans-                                                             methylcyclopentyl)-3-                                                         triphenylmethoxy-1-                                                           trans-hexenyl)tri-                                                            methyl alanate                                         144     113            lithio(4-cyclohexyl-3-                                                        triphenylmethoxy-1-                                                           trans-butenyl)trimethyl                                                       alanate                                                145     114            lithio(5-cyclohexyl-3-                                                        triphenylmethoxy-1-                                                           trans-pentenyl)tri-                                                           methyl alanate                                         146     115            lithio(6-cyclohexyl-3-                                                        triphenylmethoxy-1-                                                           trans-hexenyl)trimethyl                                                       alanate                                                147     116            lithio(4-cycloheptyl-3-                                                       triphenylmethoxy-1-                                                           trans-butenyl)trimethyl                                                       alanate                                                148     117            lithio[4-(4-methylcyclo-                                                      heptyl)-3-triphenyl-                                                          methoxy-1-trans-butenyl]                                                      trimethyl alanate                                      149     118            lithio(4-cyclooctyl-3-                                                        triphenylmethoxy-1-                                                           trans-butenyl)tri-                                                            methyl alanate                                         150     119            lithio [4-(4-methyl-                                                          cyclohexyl)-3-tri-                                                            phenylmethoxy-1-trans-                                                        butenyl]trimethyl                                                             alanate                                                151     120            lithio[4-(3-methyl-                                                           cyclohexyl)-3-triphen-                                                        ylmethoxy-1-trans-                                                            butenyl]trimethyl                                                             alanate                                                152     121            lithio[4-(1-adamantyl)-                                                       3-triphenylmethoxy-1-                                                         trans-butenyl]trimethyl                                                       alanate                                                153     122            lithio(3-cyclopentyl-3-                                                       triphenylmethoxy-1-                                                           trans-propenyl)trimeth-                                                       yl alanate                                             154     123            lithio[3-(trans-2-                                                            methylcyclopentyl)-3-                                                         triphenylmethoxy-1-                                                           trans- propenyl]tri-                                                          methyl alanate                                         155     124            lithio[3-(all trans-                                                          2,3-dimethylcyclo-                                                            pentyl)-3-triphenyl-                                                          methoxy-1-trans-                                                              propenyl]trimethyl                                                            alanate                                                156     125            lithio(3-cyclohexyl-3-                                                        triphenylmethoxy-1-                                                           trans-propenyl)tri-                                                           methyl alanate                                         157     126            lithio[3-(trans-4-                                                            methylcyclohexyl)-3-                                                          triphenylmethoxy-1-                                                           trans-propenyl)tri-                                                           methyl alanate                                         158     127            lithio(3-cyclooctyl-3-                                                        triphenylmethoxy-1-                                                           trans-propenyl)tri-                                                           methyl alanate                                         159     128            lithio[4-(2-cyclopen-                                                         enyl)3-triphenyl-                                                             methoxy-1-trans-butenyl]                                                      trimethyl alanate                                      160     129            lithio[4-(2-cyclohex-                                                         enyl)-3-triphenyl-                                                            methoxy-1-trans-buten-                                                        yl]trimethyl alanate                                   161     130            lithio[4-(3-cyclohex-                                                         enyl)-3-triphenyl-                                                            methoxy-1-trans-buten-                                                        yl]trimethyl alanate                                   162     131            lithio[1-methyl-1-(3-                                                         triphenylmethoxy-trans-                                                       1-butenyl-4)cyclo-                                                            hexyl]trimethyl alanate                                163     132            lithio[3-(I-adamantyl)-                                                       3-triphenylmethoxy-1-                                                         trans-propenyl]tri-                                                           methyl alanate                                         164     133            lithio[3-(2-cyclohex-                                                         enyl)-3-triphenyl-                                                            methoxy-1-trans-prop-                                                         enyl]trimethyl alanate                                 165     134            lithio[3-(3-cyclohex-                                                         enyl)-3-triphenylmeth-                                                        oxy-1-trans-propenyl]-                                                        trimethyl alanate                                      165A    134A           lithio[3-(2-adamantyl)-                                                       3-triphenylmethoxy-1-                                                         trans-propenyl]                                                               trimethyl alanate                                      165B    134B           lithio(3-cycloheptyl-3-                                                       triphenylmethoxy-1-                                                           trans-propenyl]trimeth-                                                       yl alanate                                             ______________________________________                                    

EXAMPLES 166-246

Treatment of the cycloalkenes listed in Table 7 below with the indicatedlithio(3-triphenylmethoxy-trans-1-alkenyl)trimethyl alanate isproductive, after acid-catalyzed de-O-tritylation of the intermediatealkyl 9-oxo-triphenylmethoxy-13-trans-prostenoates, of the product alkyl9-oxo-15-hydroxy-13-trans-prostenoates of the table. The entire sequenceis carried out by the procedures described in Example 101.

                                      TABLE 7                                     __________________________________________________________________________                      Reagent lithio (3-tri-                                                        phenylmethoxy-trans-                                                          1-alkenyl)trimethyl                                                                      Product alkyl 9-oxo-15-hydrox-13-trans-          Example                                                                            Starting Cycloalkenone                                                                     alanate of Example                                                                       prostenoates                                     __________________________________________________________________________    166  2-(6-carbethoxyhexyl)-                                                                     153        ethyl 9-oxo-15-hydroxy-16,19-methano-20-              cyclopent-2-en-1-one*   nor-13-trans-prostenoate                         167  2-(6-carbethoxyhexyl)-                                                                     136        ethyl 9-oxo-15-hydroxy-18,20-ethano-13-               cyclopent-2-en-1-one*   trans-prostenoate                                168  2-(6-carbethoxyhexyl)-                                                                     137        ethyl 9-oxo-15-hydroxy-19,20-(1,3-propano)-           cyclopent-2-en-1-one*   13-trans-prostenoate                             169  2-(6-carbethoxyhexyl)-                                                                     140        ethyl 9-oxo-15-hydroxy-16-methyl-18,20-               cyclopent-2-en-1-one*   ethano-13-trans-prostenoate                      170  2-(6-carbethoxyhexyl)-                                                                     144        ethyl 9-oxo-15-hydroxy-17,20-ethano-13-               cyclopent-2-en-1-one*   trans-prostenoate                                171  2-(6-carbethoxyhexyl)-                                                                     147        ethyl 9-oxo-15-hydroxy-17,20-(1,3-pro-                cyclopent-2-en-1-one*   pano)-13-trans-prostenoate                       172  2-(6-carbethoxyhexyl)-                                                                     150        ethyl 9-oxo-15-hydroxy-17,20-ethano-20-               cyclopent-2-en-1-one*   methyl-13-trans-prostenoate                      173  2-(6-carbethoxyhexyl)-                                                                     152        ethyl 9-oxo-15-hydroxy-17,18,19,20-tetra-             cyclopent-2-en-1-one*   nor-16-(1-adamantyl)-13-trans-prostenoate        174  2-(6-carbo-n-decyloxy-                                                                     153        decyl 9-oxo-15-hydroxy-20-nor-16,19-                  hexyl)cyclopent-2-en-1- methano-13-trans-prostenoate                          one (Example 7)                                                          175  2-(6-carbethoxyhexyl)-                                                                     156        ethyl 9-oxo-15-hydroxy-16,20-methano-13-              cyclopent-2-en-1-one*   trans-prostenoates                               176  2-(6-carbethoxyhexyl)-                                                                     157        ethyl 9-oxo-15-hydroxy-16,19-ethano-13-               cyclopent-2-en-1-one*   trans-prostenoates                               177  2-(6-carbethoxyhexyl)-                                                                     158        ethyl 9-oxo-15-hydroxy-16,20-(1,3-propano)-           cyclopent-2-en-1-one*   13-trans-prostenoate                             178  2-(6-carbethoxyhexyl)-                                                                     159        ethyl 9-oxo-15-hydroxy-17,20-methano-13-              cyclopent-2-en-1-one*   trans,18-prostadienoate                          179  2-(6-carbethoxyhexyl)-                                                                     160        ethyl 9-oxo-15-hydroxy-17,20-ethano-13-               cyclopent-2-en-1-one*   trans,18-prostadienoate                          180  2-(6-carbethoxyhexyl)-                                                                     161        ethyl 9-oxo-15-hydroxy-17,20-ethano-13-               cyclopent-2-en-1-one*   trans,19-prostadienoate                          181  2-(6-carbethoxyhexyl)-                                                                     164        ethyl 9-oxo-15-hydroxy-16,20-methano-13-              cyclopent-2-en-1-one*   trans,17-prostadienoate                          182  2-(6-carbethoxyhexyl)-                                                                     165        ethyl 9-oxo-15-hydroxy-16,20-methano-13-              cyclopent-2-en-1-one*   trans,18-prostadienoate                          183  2-(6-carbethoxyhexyl)-                                                                     163        ethyl 9-oxo-15-hydroxy-16,17,18,19,20-                cyclopent-2-en-1-one*   pentanor-15-(1-adamantyl)-13-trans-                                           prostenoate                                      184  2-(3-carbethoxypropyl)-                                                                    138        ethyl 9-oxo-15,6,7-trinor-15-hydroxy-                 cyclopent-2-en-1-one*   20,20-(1,4-butano)-13-trans-prostenoate          185  2-(4-carbethoxybutyl)-                                                                     139        ethyl 9-oxo-6,7-dinor-15-hydroxy-20-                  cyclopent-2-en-1-one*   cyclopentyl-13-trans-prostenoate                 186  2-(8u-carbethoxyoctyl)-                                                                    142        ethyl 9-oxo-7a,7b-bishomo-15-hydroxy-18-              cyclopent-2-en-1-one*   methyl-17,20-methano-13-trans-prostenoate        187  2-(8-carbethoxyoctyl)-                                                                     157        ethyl 9-oxo-7a,7b-bishomo-15-hydroxy-16,19-           cyclopent-2-en-1-one*   ethano-13-trans-prostenoate                      188  2-(6-carbethoxyhexyl)-                                                                     151        ethyl 9-oxo-10a-homo-15-hydroxy-17,19-                cyclohex-2-en-1-one*    (1,3-propano)-13-trans-prostenoate               189  2-(7-carbethoxyhexyl)-                                                                     152        ethyl 9-oxo-10a-homo-15-hydroxy-17,18,19-             cyclohex-2-en-1-one*    20-tetranor-16-(1-adamantyl)-13-trans-                                        prostenoate                                      190  2-(6-carbethoxyoctyl)-                                                                     144        ethyl 9-oxo-2-ethyl-15-hydroxy-17,20-                 cyclopent-2-en-1-one*   ethano-13-trans-prostenoate                      191  2-(6-carbethoxyoctyl)-                                                                     159        ethyl 9-oxo-2-ethyl-15-hydroxy-17,20-                 cyclopent-2-en-1-one*   methano-13-trans,18-prostadienoate               192  2-(6-carbethoxyoctyl)-                                                                     165        ethyl 9-oxo-2-ethyl-15-hydroxy-16,20-                 cyclopent-2-en-1-one*   methano-13-trans,18-prostadienoate               193  2-(6-carbethoxyhep-                                                                        141        ethyl 9-oxo-2-methyl-15-hydroxy-16-ethyl-             tyl)cyclopent-2-en-1-   19,20-(1,3-propano)-13-trans-prostenoate              one (Example 3)                                                          194  2-(6-carbethoxyhep-                                                                        135        ethyl 9-oxo-2-methyl-15-hydroxy-17,19-                tyl)cyclopent-2-en-1-   methano-20-nor-13-trans-prostenoate                   one (Example 3)                                                          195  2-(6-carbethoxyhep-                                                                        158        ethyl 9-oxo-2-methyl-15-hydroxy-16,20-                tyl)cyclopent-2-en-1-   (1,3-propano)-13-trans-prostenoate                    one (Example 3)                                                          196  2-(6-carbethoxy-5,5-                                                                       156        ethyl 9-oxo-3,3-dimethyl-15-hydroxy-16,20-            dimethylhexyl)cyclo-    methano-13-trans-prostenoate                          pent-2-en-1-one*                                                         197  2-(6-carbethoxy-5,5-                                                                       149        ethyl 9-oxo-3,3-dimethyl-15-hydroxy-17,20-            dimethylhexyl)cyclo-    (1,4-butano)-13-trans-prostenoate                     pent-2-en-1-one*                                                         198  2-(6-carbethoxy-5,5-                                                                       165        ethyl 9-oxo-3,3-dimethyl-15-hydroxy-16,20-            dimethylhexyl)cyclo-    methano-13-trans,18-prostadienoate                    pent-2-en-1-one*                                                         199  2-(6-carbethoxy-5-oxa-                                                                     157        ethyl 9-oxo-3-oxa-15-hydroxy-16,19-ethano-            hexyl)cyclopent-2-en-1- 13-trans-prostenoate                                  one*                                                                     200  2-(6-carbethoxy-5-oxa-                                                                     152        ethyl 9-oxo-3-oxa-15-hydroxy-17,18,19,20-             hexyl)cyclopent-2-en-   tetranor-16-(1-adamantyl)-13-trans-                   1-one*                  prostenoate                                      201  2-(6-carbethoxy-5-oxa-                                                                     143        ethyl 9-oxo-3-oxa-15-hydroxy-20-methyl-               hexyl)cyclopent-2-en-   19,20-(1,3-propano)-13-trans-prostenoate              1-one*                                                                   202  2-(6-carbethoxy-5-oxa-                                                                     141        ethyl 9-oxo-3-oxa-15-hydroxy-16-ethyl-19,20-                                  7                                                     hexyl)cyclopent-2-en-   (1,3-propano)-13-trans-prostenoate                    1-one*                                                                   203  2-(6-carbethoxy-5-oxa-                                                                     161        ethyl 9-oxo-3-oxa-15-hydroxy-17,20-ethano-            hexyl)cyclopent-2-en-   13-trans,19-prostadienoate                            1-one*                                                                   204  2-(6-carbethoxy-5-thia-                                                                    165B       ethyl 9-oxo-3-thia-15-hydroxy-16,20-ethano-           hexyl)cyclopent-2-en-   13-trans-prostenoate                                  1-one*                                                                   205  2-(6-carbethoxy-5-thia-                                                                    140        ethyl 9-oxo-3-thia-15-hydroxy-16-methyl-              hexyl)cyclopent-2-en-   18,20-ethano-13-trans-prostenoate                206  2-(6-carbethoxy-5-thia-                                                                    154        ethyl 9-oxo-3-thia-15-hydroxy-17-methyl-              hexyl)cyclopent-2-en-   20-nor-16,19-methano-13-trans-prostenoate             1-one*                                                                   207  2-(6-carbethoxy-5-thia-                                                                    144        ethyl 9-oxo-3-thia-15-hydroxy-17,20-                  hexyl)cyclopent-2-en-1- ethano-13-trans-prostenoate                           one*                                                                     208  2-(6-carbethoxy-6-fluoro-                                                                  148        ethyl 9-oxo-2-fluoro-15-hydroxy-20-methyl-            hexyl)cyclopent-2-en-1- 17,20-(1,3-propano)-13-trans-prostenoate              one (Example 1)                                                          209  2-(6-carbethoxy-6-fluoro-                                                                  165A       ethyl 9-oxo-2-fluoro-15-hydroxy-16,17,18,-            hexyl)cyclopent-2-en-1- 19,20-pentanor-15-(2-adamantyl)-13-trans-             one (Example 1)         prostenoate                                      210  2-(6-carbethoxy-6-phenyl-                                                                  156        ethyl 9-oxo-2-phenyl-15-hydroxy-16,20-                hexyl)cyclopent-2-en-1- methano-13-trans-prostenoate                          one (Example 2)                                                          211  2-(6-carbo-n-butoxyhex-                                                                    165B       butyl 9-oxo-15-hydroxy-16,20-ethano-13-               yl)cyclopent-2-en-1-    trans-prostenoate                                     one (Example 4)                                                          212  2-(6-carboisopropoxy-                                                                      165A       isopropyl 9-oxo-15-hydroxy-16,17,18,19,20-            hexyl)cyclopent-2-en-1- pentanor-15-(2-adamantyl)-13-trans-proten-            one (Example 5)         oate                                             213  2-(5-carbomethoxy-2-cis-                                                                   136        methyl 9-oxo-15-hydroxy-4-nor-18,20-ethano-           pentnyl)cyclopent-2-en- 5-cis,13-trans-prostadienoate                         1-one (Example 28)                                                       214  2-(5-carbomethoxy-2-cis-                                                                   145        methyl 9-oxo-15-hydroxy-4-nor-18,20-                  pentenyl)cyclopent-2-   (1,3-propano)-5-cis,13-trans-prosta-                  en-1-one (Example 28)   dienoate                                         215  2-(5-carbomethoxy-2-cis-                                                                   164        methyl 9-oxo-15-hydroxy-4-nor-16,20-                  pentyl)cyclopent-2-     methano-5-cis,13-trans,17-protatrienoate              en-1-one (Example 28)                                                    216  2-(7-carbomethoxy-2-cis-                                                                   101        methyl 9-oxo-15-hydroxy-4a-homo-17,20-                heptenyl)cyclopent-2-   methano-5-cis,13-trans-prostadienoate                 en-1-one (Example 29)                                                    217  2-(7-carbomethoxy-2-cis-                                                                   163        methyl 9-oxo-15-hydroxy-4a-homo-16,17,-               heptenyl)cyclopent-2-   18,19,20-pentanor-15-(1-adamantyl)-5-                 en-1-one (Example 29)   cis,13-trans-prostadienoate                      218  2-(7-carbomethoxy-2-cis-                                                                   156        methyl 9-oxo-15-hydroxy-4a-homo-16,20-                heptenyl)cyclopent-2-   methano-5-cis,13-trans-prostadienoate                 en-1-one (Example 29)                                                    219  2-(6-carbomethoxy-2-cis-                                                                   136        methyl 9-oxo-15-hydroxy-18,20-ethano-                 hexenyl)cyclopent-2-en- 5-cis,13-trans-prostadienoate                         1-one (Example 14)                                                       220  2-(6-carbomethoxy-2-cis-                                                                   138        methyl 9-oxo-15-hydroxy-20,20-(1,4-                   hexenyl)cyclopent-2-en- butano)-5-cis,13-trans-prostadienoate                 1-one (Example 14)                                                       221  2-(6-carbomethoxy-2-                                                                       139        methyl 9-oxo-15-hydroxy-20-cyclopentyl-               cis-hexenyl)cyclopent-  cis,13-trans-prostadienoate                           2-en-1-one (Example 14)                                                  222  2-(6-carbomethoxy-2-                                                                       141        methyl 9-oxo-15-hydroxy-16-ethyl-19,20-               cis-hexenyl)cyclopent-  (1,3-propano)-5-cis,13-trans-prostadienoate           2-en-1-one (Example 14)                                                  223  2-(6-carbomethoxy-2-                                                                       144        methyl 9-oxo-15-hydroxy-17,20-ethano-5-               cis-hexenyl)cyclopent-  cis,13-trans-prostadienoate                           2-en-1-one (Example 14)                                                  224  2-(6-carbomethoxy-2-                                                                       146        methyl 9-oxo-15-hydroxy-19,20-(1,4-butano)-           cis-hexenyl)cyclopent-  5-cis,13-trans-prostadienoate                         2-en-1-one (Example 14)                                                  225  2-(6-carbomethoxy-2-                                                                       147        methyl 9-oxo-15-hydroxy-17,20-(1,3-propano)-                                  2                                                     cis-hexenyl)cyclopent-  5-cis,13-trans-prostadienoate                         2-en-1-one (Example 14)                                                  226  2-(6-carbomethoxy-2-                                                                       150        methyl 9-oxo-15-hydroxy-20-methyl-17,20-              cis-hexenyl)cyclopent-  ethano-5-cis,13-trans-prostadienoate                  2-en-1-one (Example 14)                                                  227  2-(6-carbomethoxy-2-                                                                       152        methyl 9-oxo-15-hydroxy-17,18,19,20-tetra-            cis-hexenyl)cyclopent-  nor-16-(1-adamantyl)-5-cis,13-trans-prosta-           2-en-1-one (Example 14) dienoate                                         228  2-(6-carbomethoxy-2-                                                                       155        methyl 9-oxo-15-hdyroxy-17-methyl-20-nor-             cis-hexenyl)cyclopent-  16,18-ethano-5-cis,13-trans-prostadienoate            2-en-1-one (Example 14)                                                  229  2-(6-carbomethoxy-2-                                                                       156        methyl 9-oxo-15-hydroxy-16,20-methano-5-              cis-hexenyl)cyclopent-  cis,13-trans-prostadienoate                           2-en-1-one (Example 14)                                                  230  2-(6-carbomethoxy-2-                                                                       101        methyl 9-oxo-15-hydroxy-17,20-methano-5-              cis-hexenyl)cyclopent-  cis,13-trans-prostadienoate                           2-en-1-one (Example 14)                                                  231  2-(6-carbomethoxy-2-                                                                       157        methyl 9-oxo-15-hydroxy-16,19-ethano-5-               cis-hexenyl)cyclopent-  cis,13-trans-prostadienoate                           2-en-1-one (Example 14)                                                  232  2-(6-carbomethoxy-2-                                                                       158        methyl 9-oxo-15-hydroxy-16,20-(1,3-pro-               cis-hexenyl)cyclopent-  pano)-5-cis,13-trans-prostadienoate                   2-en-1-one (Example 14)                                                  233  2-(6-carbomethoxy-2-                                                                       165B       methyl 9-oxo-15-hydroxy-16,20-ethano-5-               cis-hexenyl)cyclopent-  cis,13-trans-prostadienoate                           2-en-1-one (Example 14)                                                  234  2-(6-carbomethoxy-2-                                                                       163        methyl 9-oxo-15-hydroxy-16,17,18,19,20-               cis-hexenyl)cyclopent-  pentanor-15-(1-adamantyl)-5-cis,13-trans-             2-en-1-one (Example 14) prostadienoate                                   235  2-(6-carbomethoxy-2-                                                                       165A       methyl 9-oxo-15-hdyroxy-16,17,18,19,20-               cis-hexenyl)cyclopent-  pentanor-15-(2-adamantyl)-5-cis,13-trans-             2-en-1-one (Example 14) prostadienoate                                   236  2-(6-carbomethoxy-2-                                                                       162        methyl 9-oxo-15-hydroxy-16-methyl-16,20-              cis-hexenyl)cyclopent-  methano-5-cis,13-trans-prostadienoate                 2-en-1-one (Example 14)                                                  237  2-(6-carbomethoxy-2-                                                                       159        methyl 9-oxo-15-hydroxy-17,20-methano-5-              cis-hexenyl)cyclopent-  cis,13-trans,18-prostatrienoate                       2-en-1-one (Example 14)                                                  238  2-(6-carbomethoxy-2-                                                                       160        methyl 9-oxo-15-hydroxy-17,20-ethano-5-               cis-hexenyl)cyclopent-  cis,13-trans,18-prostatrienoate                       2-en-1-one (Example 14)                                                  239  2-(6-carbomethoxy-2-                                                                       161        methyl 9-oxo-15-hydroxy-17,20-ethano-5-               cis-hexenyl)cyclopent-  cis,13-trans-19-prostatrienoate                       2-en-1-one (Example 14)                                                  240  2-(6-carbomethoxy-2-                                                                       164        methyl 9-oxo-15-hydroxy-16,20-methano-5-              cis-hexenyl)cyclopent-  cis,13-trans,17-prostatrienoate                       2-en-1-one (Example 14)                                                  241  2-(6-carbomethoxy-2-                                                                       165        methyl 9-oxo-15-hydroxy-16,20-methano-5-              cis-hexenyl)cyclopent-  cis,13-trans-18-prostatrienoate                       2-en-1-one (Example 14)                                                  242  2-(8-carbomethoxy-2-                                                                       162        methyl 9-oxo-15-hydroxy-4a,4b-bishomo-17-             cis-octenyl)cyclopent-  methyl-17,20-methano-5-cis,13-trans-                  2-en-1-one (Example 30) prostadienoate                                   243  2-(8-carbomethoxy-2-                                                                       142        methyl 9-oxo-15-hydroxy-4a,4b-bishomo-18-             cis-octenyl)cyclopent-  methyl-17,20-methano-5-cis,13-trans-                  2-en-1-one (Example 30) prostadienoate                                   244  2-(8-carbomethoxy-2-                                                                       165B       methyl 9-oxo-15-hydroxy-4a,4b-bishomo-                cis-octenyl)cyclopent-  16,20-ethano-5-cis,13-trans-prostadienoate            2-en-1-one (Example 30)                                                  245  2-(8-carbomethoxy-2-                                                                       151        methyl 9-oxo-15-hydroxy-4a,4b-bishomo-                cis-octenyl)cyclopent-  17,19-(1,3-propano)-5-cis,13-trans-pros-              2-en-1-one (Example 30) tadienoate                                       246  2-(8-carbomethoxy-2-                                                                       157        methyl 9-oxo-15-hydroxy-4a,4b-bishomo-16,19-                                  5                                                     cis-octenyl)cyclopent-  ethano-5-cis,13-trans-prostadienoate                  2-en-1-one (Example 30)                                                  __________________________________________________________________________

EXAMPLES 247-324

Saponification of the alkyl prostenoates listed in Table 8 below by theprocedure described in Example 102 furnishes the product prostenoicacids of the table.

                  TABLE 8                                                         ______________________________________                                                Starting alkyl                                                                              Product 9-oxo-15-hy-                                    Ex-     prostenoate of                                                                              droxy-13-trans-prosten-                                 ample   Example       oic acids                                               ______________________________________                                        247     166           9-oxo-15-hydroxy-16,19-                                                       methano-20-nor-13-                                                            trans-prostenoic acid                                   248     167           9-oxo-15-hydroxy-18,20-                                                       ethano-13-trans-pros-                                                         tenoic acid                                             249     168           9-oxo-15-hydroxy-19,20-                                                       1,3-propano-13-trans-                                                         prostenoic acid                                         250     169           9-oxo-15-hydroxy-16-                                                          methyl-18,20-ethano-                                                          13-trans-prostenoic                                                           acid                                                    251     170           9-oxo-15-hydroxy-17,20-                                                       ethano-13-trans-pros-                                                         tenoic acid                                             252     171           9-oxo-15-hydroxy-17,20-                                                       1,3-propano-13-trans-                                                         prostenoic acid                                         253     172           9-oxo-15-hydroxy-17,20-                                                       ethano-20-methyl-13-                                                          trans-prostenoic acid                                   254     173           9-oxo-15-hydroxy-17,18,-                                                      19,20-tetranor-16-(1-                                                         adamantyl)-13-trans-                                                          prostenoic acid                                         255     175           9-oxo-15-hydroxy-16,20-                                                       methano-13-trans-pros-                                                        tenoic acid                                             256     176           9-oxo-15-hydroxy-16,19-                                                       ethano-13-trans-pros-                                                         tenoic acid                                             257     177           9-oxo-15-hydroxy-16,20-                                                       (1,3-propano)-13-trans-                                                       prostenoic acid                                         258     178           9-oxo-15-hydroxy-17,20-                                                       methano-13-trans,18-                                                          prostadienoic acid                                      259     179           9-oxo-15-hydroxy-17,20-                                                       ethano-13-trans,18-                                                           prostadienoic acid                                      260     180           9-oxo-15-hydroxy-17,20-                                                       ethano-13-trans,19-                                                           prostadienoic acid                                      261     181           9-oxo-15-hydroxy-17,20-                                                       methano-13-trans,17-                                                          prostadienoic acid                                      262     182           9-oxo-15-hydroxy-16,20-                                                       methano-13-trans,18-                                                          prostadienoic acid                                      263     183           9-oxo-15-hydroxy-16,17-                                                       18,19,20-pentanor-15-                                                         (1-adamantyl)-13-trans-                                                       prostenoic acid                                         264     184           9-oxo-5,6,7-trinor-15-                                                        hydroxy-20,20-(1,4-                                                           butano)-13-trans-pros-                                                        tenoic acid                                             265     185           9-oxo-6,7-dinor-15-hy-                                                        droxy-20-cyclopentyl-                                                         13-trans-prostenoic                                                           acid                                                    266     186           9-oxo-7a,7b-bishomo-15-                                                       hydroxy-18-methyl-17,-                                                        20-methano-13-trans-                                                          prostenoic acid                                         267     187           9-oxo-7a,7b-bishomo-15-                                                       hydroxy-16,19-ethano-                                                         13-trans-prostenoic                                                           acid                                                    268     188           9-oxo-10a-homo-15-hy-                                                         droxy-17,19-(1,3-pro-                                                         pano)-13-trans-prosten-                                                       oic acid                                                269     189           9-oxo-10a-homo-15-hy-                                                         droxy-17,18,19,20-te-                                                         tra-nor-16-(1-adamantyl)-                                                     13-trans-prostenoic                                                           acid                                                    270     190           9-oxo-2-ethyl-15-hy-                                                          droxy-17,20-ethano-13-                                                        trans-prostenoic acid                                   271     191           9-oxo-2-ethyl-15-hy-                                                          droxy-17,20-methano-13-                                                       trans,18-prostadienoic                                                        acid                                                    272     192           9-oxo-2-ethyl-15-hy-                                                          droxy-16,20-methano-13-                                                       trans,18-prostadienoic                                                        acid                                                    273     193           9-oxo-2-methyl-15-hy-                                                         droxy-16-ethyl-19,20-                                                         (1,3-propano)-13-                                                             trans-prostenoic acid                                   274     194           9-oxo-2-methyl-15-hy-                                                         droxy-17,19-methano-20-                                                       nor-13-trans-prosten-                                                         oic acid                                                275     195           9-oxo-2-methyl-15-hy-                                                         droxy-16,20-(1,3-pro-                                                         pano)-13-trans-prosten-                                                       oic acid                                                276     196           9-oxo-3,3-dimethyl-15-                                                        hydroxy-16,20-methano-                                                        13-trans-prostenoic                                                           acid                                                    277     197           9-oxo-3,3-dimethyl-15-                                                        hydroxy-17,20-(1,4-bu-                                                        tano)-13-trans-prosten-                                                       oic acid                                                278     198           9-oxo-3,3-dimethyl-15-                                                        hydroxy-16,20-methano-                                                        13-trans,18-prostadi-                                                         enoic acid                                              279     199           9-oxo-3-oxa-15-hydroxy-                                                       16,19-ethano-13-trans-                                                        prostenoic acid                                         280     200           9-oxo-3-oxa-15-hydroxy-                                                       17,18,19,20-tetranor-                                                         16-(1-adamantyl)-13-                                                          trans-prostenoic acid                                   281     201           9-oxo-3-oxa-15-hydroxy-                                                       20-methyl-19,20-(1,3-                                                         propano)-13-trans-                                                            prostenoic acid                                         282     202           9-oxo-3-oxa-15-hydroxy-                                                       16-ethyl-19,20-(1,3-                                                          propano)-13-trans-                                                            prostenoic acid                                         283     203           9-oxo-3-oxa-15-hydroxy-                                                       17,20-ethano-13-trans,                                                        19-prostadienoic acid                                   284     204           9-oxo-3-thia-15-hydroxy-                                                      16,20-ethano-13-trans-                                                        prostenoic acid                                         285     205           9-oxo-3-thia-15-hydroxy-                                                      16-methyl-18,20-ethano-                                                       13-trans-prostenoic                                                           acid                                                    286     206           9-oxo-3-thia-15-hydroxy-                                                      17-methyl-20-nor-16,19-                                                       methano-prostenoic acid                                 287     207           9-oxo-3-thia-15-hydroxy-                                                      17,20-ethano-13-trans-                                                        prostenoic acid                                         288     208           9-oxo-2-fluoro-15-hy-                                                         droxy-20-methyl-17,20-                                                        (1,3-propano)-13-                                                             trans-prostenoic acid                                   289     209           9-oxo-2-fluoro-15-hy-                                                         droxy-16,17,18,19,20-                                                         pentanor-15-(2-adaman-                                                        tyl)-13-trans-prosten-                                                        oic acid                                                290     210           9-oxo-2-phenyl-15-hy-                                                         droxy-16,20-methano-13-                                                       trans-prostenoic acid                                   291     213           9-oxo-15-hydroxy-4-nor-                                                       18,20-ethano-5-cis,13-                                                        trans-prostadienoic                                                           acid                                                    292     214           9-oxo-15-hydroxy-4-nor-                                                       18,20-(1,3-propano)-5-                                                        cis,13-trans-prostadi-                                                        enoic acid                                              293     215           9-oxo-15-hydroxy-4-nor-                                                       16,20-methano-5-cis,13-                                                       trans,17-prostatrieno-                                                        ic acid                                                 294     216           9-oxo-15-hydroxy-4a-                                                          homo-17,20-methano-5-                                                         cis,13-trans-prostadi-                                                        enoic acid                                              295     217           9-oxo-15-hydroxy-4a-ho-                                                       mo-16,17,18,19,20-penta-                                                      nor-15-(1-adamantyl)-5-                                                       cis,13-trans-prostadi-                                                        enoic acid                                              296     218           9-oxo-15-hydroxy-4a-ho-                                                       mo-16,20-methano-5-cis,-                                                      13-trans-prostadienoic                                                        acid                                                    297     219           9-oxo-15-hydroxy-18,20-                                                       ethano-5-cis,13-trans-                                                        prostadienoic acid                                      298     220           9-oxo-15-hydroxy-20,20-                                                       (1,4-butano)-5-cis,13-                                                        trans-prostadienoic                                     299     221           9-oxo-15-hydroxy-20-cy-                                                       clopentyl-5-cis,13-                                                           trans-prostadienoic                                                           acid                                                    300     222           9-oxo-15-hydroxy-16-                                                          ethyl-19,20-(1,3-pro-                                                         pano)-5-cis,13-trans-                                                         prostadienoic acid                                      301     223           9-oxo-15-hydroxy-17,20-                                                       ethano-5-cis,13-trans-                                                        prostadienoic acid                                      302     224           9-oxo-15-hydroxy-19,20-                                                       (1,4-butano)-5-cis,13-                                                        trans-prostadienoic                                                           acid                                                    303     225           9-oxo-15-hydroxy-17,20-                                                       (1,3-propano)-5-cis,13-                                                       trans-prostadienoic                                                           acid                                                    304     226           9-oxo-15-hydroxy-20-                                                          methyl-17,20-ethano-5-                                                        cis,13-trans-prosta-                                                          dienoic acid                                            305     227           9-oxo-15-hydroxy-17,18,-                                                      19,20-tetranor-16-(1-                                                         adamantyl)-5-cis,13-                                                          trans-prostadienoic                                                           acid                                                    306     228           9-oxo-15-hydroxy-17-                                                          methyl-20-nor-16,18-                                                          ethano-5-cis,13-trans-                                                        prostadienoic acid                                      307     229           9-oxo-15-hydroxy-16,20-                                                       methano-5-cis,13-trans-                                                       prostadienoic acid                                      308     230           9-oxo-15-hydroxy-17,20-                                                       methano-5-cis,13-trans-                                                       prostadienoic acid                                      309     231           9-oxo-15-hydroxy-16,19-                                                       ethano-5-cis,13-trans-                                                        prostadienoic acid                                      310     232           9-oxo-15-hydroxy-16,20-                                                       (1,3-propano)-5-cis,13-                                                       trans-prostadienoic                                                           acid                                                    311     233           9-oxo-15-hydroxy-16,20-                                                       ethano-5-cis,13-trans-                                                        prostadienoic acid                                      312     234           9-oxo-15-hydroxy-16,17,-                                                      18,19,20-pentanor-15-(1-                                                      adamantyl)-5-cis,13-                                                          trans-prostadienoic                                                           acid                                                    313     235           9-oxo-15-hydroxy-16,17,-                                                      18,19,20-pentanor-15-(2-                                                      adamantyl)-5-cis,13-                                                          trans-prostadienoic                                                           acid                                                    314     236           9-oxo-15-hydroxy-16-                                                          methyl-16,20-methano-                                                         5-cis,13-trans-prosta-                                                        dienoic acid                                            315     237           9-oxo-15-hydroxy-17,20-                                                       methano-5-cis,13-trans,-                                                      18-prostatrienoic acid                                  316     238           9-oxo-15-hydroxy-17,20-                                                       ethano-5-cis,13-trans,                                                        18-prostatrienoic acid                                  317     239           9-oxo-15-hydroxy-17,20-                                                       ethano-5-cis,13-trans,                                                        19-prostatrienoic acid                                  318     240           9-oxo-15-hydroxy-16,20-                                                       methano-5-cis,13-trans,                                                       17-prostatrienoic acid                                  319     241           9-oxo-15-hydroxy-16,20-                                                       methano-5-cis,13-trans,                                                       18-prostatrienoic acid                                  320     242           9-oxo-15-hydroxy-4a,4b-                                                       bishomo-17-methyl-17,-                                                        20-methano-5-cis,13-                                                          trans-prostadienoic                                                           acid                                                    321     243           9-oxo-15-hydroxy-4a,4b-                                                       bishomo-18-methyl-17,-                                                        20-methano-5-cis,13-                                                          trans-prostadienoic                                                           acid                                                    322     244           9-oxo-15-hydroxy-4a,4b-                                                       bishomo-16,20-ethano-                                                         5-cis,13-trans-prosta-                                                        dienoic acid                                            323     245           9-oxo-15-hydroxy-4a,4b-                                                       bishomo-17,19-(1,3-                                                           propano)-5-cis,13-trans-                                                      prostadienoic acid                                      324     246           9-oxo-15-hydroxy-4a,4b-                                                       bishomo-16,19-ethano-                                                         5-cis,13-trans-prosta-                                                        dienoic acid                                            ______________________________________                                    

EXAMPLE 325 Preparation of9α,15-dihydroxy-17,20-methano-13-trans-prostenoic acid

To a solution of 433 mg. of9-oxo-15-hydroxy-17,20-methano-13-trans-prostenoic acid (Example 102) in4.5 ml. of tetrahydrofuran, stirred in an ice bath under nitrogenatmosphere, is added dropwise 3.7 ml. of 0.76 M lithiumperhydro-9b-boraphenalyl hydride. After 40 minutes at 0° C. there isadded 1.62 ml. of 3 N sodium hydroxide followed by 1.62 ml. of 30%hydrogen peroxide. Ether is added and the resulting solution isacidified with 2 N hydrochloric acid. The ether layer is washed severaltimes with saturated sodium chloride solution, dried with anhydrousmagnesium sulfate and then to dryness to give the subject product as anoil.

EXAMPLES 326-403

Treatment of the 9-oxo-derivatives designated in Table 9 below withlithium perhydro-9b-boraphenalyl hydride by the procedure described inExample 325 provides the 9α,15- dihydroxy derivatives of the table.

                  Table 9                                                         ______________________________________                                                Starting 9-oxo-                                                               15-hydroxy-13-                                                                              Product 9-α,15-                                   Ex-     trans-prostenoic                                                                            dihydroxy-13-                                           ample   acid of Example                                                                             trans-prostenoic acids                                  ______________________________________                                        326     247           9α,15-dihydroxy-16,19-                                                  methano-20-nor-13-                                                            trans-prostenoic acid                                   327     248           9α,15-dihydroxy-18,20-                                                  ethano-13-trans-pros-                                                         tenoic acid                                             328     249           9α,15-dihydroxy-19,20-                                                  (1,3-propano)-13-trans-                                                       prostenoic acid                                         329     250           9α,15-dihyroxy-16-                                                      methyl-18,20-ethano-                                                          13-trans-prostenoic                                                           acid                                                    330     251           9α,15-dihydroxy-17,20-                                                  ethano-13-trans-pros-                                                         tenoic acid                                             331     252           9α,15-dihydroxy-17,20-                                                  (1,3-propano)-13-trans-                                                       prostenoic acid                                         332     253           9α,15-dihydroxy-17,20-                                                  ethano-20-methyl-13-                                                          trans-prostenoic acid                                   333     254           9α,15-dihydroxy-17,18,-                                                 19,20-tetranor-16-(1-                                                         adamantyl)-13-trans-                                                          prostenoic acid                                         334     255           9α,15-dihydroxy-16,20-                                                  methano-13-trans-                                                             prostenoic acid                                         335     256           9α,15-dihydroxy-16,19-                                                  ethano-13-trans-prosten-                                                      oic acid                                                336     257           9α,15-dihydroxy-16,20-                                                  (1,3-propano)-13-trans-                                                       prostenoic acid                                         337     258           9α,15-dihydroxy-17,20-                                                  methano-13-trans,18-                                                          prostadienoic acid                                      338     259           9α,15-dihydroxy-17,20-                                                  ethano-13-trans-18-                                                           prostadienoic acid                                      339     260           9α,15-dihydroxy-17,20-                                                  ethano-13-trans,19-                                                           prostadienoic acid                                      340     261           9α,15-dihydroxy-16,20-                                                  methano-13-trans,17-                                                          prostadienoic acid                                      341     262           9α,15-dihydroxy-16,20-                                                  methano-13-trans,18-                                                          prostadienoic acid                                      342     263           9α,15-dihydroxy-16,17,-                                                 18,19,20-pentanor-15-                                                         (1-adamantyl)-13-trans-                                                       prostenoic acid                                         343     264           5,6,7-trinor-9α,15-                                                     dihydroxy-20,20-(1,4- -  buatno)-13-trans-pros-                               tenoic acid                                             344     265           6,7-dinor-9α,15-di-                                                     hydroxy-20-cyclopentyl-                                                       13-trans-prostenoic                                                           acid                                                    345     266           7a,7b-bishomo-9α,15-                                                    dihydroxy-18-methyl-                                                          17,20-methano-13-trans-                                                       prostenoic acid                                         346     267           7a,7b-bishomo-9α,15-                                                    dihydroxy-16,19-ethano-                                                       13-trans-prostenoic                                                           acid                                                    347     268           10a-homo-9α,15-di-                                                      hydroxy-17,19-(1,3-                                                           propano)-13-trans-                                                            prostenoic acid                                         348     269           10a-homo-9α,15-di-                                                      hydroxy-17,18,19,20-                                                          tetranor-16-(1-adaman-                                                        tyl)-13-trans-pros-                                                           tenoic acid                                             349     270           2-ethyl-9α,15-di-                                                       hydroxy-17,20-ethano-13-                                                      trans-prostenoic acid                                   350     271           2-ethyl-9α,15-di-                                                       hydroxy-17,20-methano-                                                        13-trans,18-prostadien-                                                       oic acid                                                351     272           2-ethyl-9α,15-di-                                                       hydroxy-16,20-methano-                                                        13-trans,18-prostadien-                                                       oic acid                                                352     273           2-methyl-9α,15-di-                                                      hydroxy-16-ethyl-19,20-                                                       (1,3-propano)-13-trans-                                                       prostenoic acid                                         353     274           2-methyl-9α,15-di-                                                      hydroxy-17,19-methano-                                                        20-nor-13-trans-pros-                                                         tenoic acid                                             354     275           2-methyl-9α,15-di-                                                      hydroxy-16,20-(1,3-                                                           propano)-13-trans-pros-                                                       tenoic acid                                             355     276           3,3-dimethyl-9α,15di-                                                   hydroxy-16,20-methano-                                                        13-trans-prostenoic                                                           acid                                                    356     277           3,3-dimethyl-9α,15-di-                                                  hydroxy-17,20-(1,4-                                                           butano)-13-trans-pros-                                                        tenoic acid                                             357     278           3,3-dimethyl-9α,15-                                                     dihydroxy-16,20-methano-                                                      13-trans,18-prostadien-                                                       oic acid                                                358     279           3-oxa-9α,15-dihydroxy-                                                  16,19-ethano-13-trans-                                                        prostenoic acid                                         359     280           3-oxa-9α,15-dihydroxy-                                                  17,18,19,20-tetranor-                                                         16-(1-adamantyl)-13-                                                          trans-prostenoic acid                                   360     281           3-oxa-9α,15-dihydroxy-                                                  20-methyl-19,20-(1,3-                                                         propano)-13-trans-                                                            prostenoic acid                                         361     282           3-oxa-9α,15-dihydroxy-                                                  16-ethyl-19,20-(1,3-                                                          propano)-13-trans-                                                            prostenoic acid                                         362     283           3-oxa-9α,15-dihydroxy-                                                  17,20-ethano-13-trans,-                                                       19-prostadienoic acid                                   363     284           3-thia-9α,15-dihydroxy-                                                 16,20-ethano-13-trans-                                                        prostenoic acid                                         364     285           3-thia-9α,15-dihydroxy-                                                 16-methyl-18,20-ethano-                                                       13-trans-prostenoic acid                                365     285           3-thia-9α,15-dihydroxy-                                                 17-methyl-20-nor-16,19-                                                       methano-13-trans-                                                             prostenoic acid                                         366     287           3-thia-9α,15-dihydroxy-                                                 17,20-ethano-13-trans-                                                        prostenoic acid                                         367     288           2-fluoro-9α,15-di-                                                      hydroxy-20-methyl-17,-                                                        20-(1,3-propano)-13-                                                          trans-prostenoic acid                                   368     289           2-fluoro-16,17,18,19,-                                                        20-pentanor-15-(2-                                                            adamantyl)-13-trans-                                                          prostenoic acid                                         369     290           2-phenyl-9α,15-di-                                                      hydroxy-16,20-methano- -  13-trans-prostenoic                                 acid                                                    370     291           9α,15-dihydroxy-4-nor-                                                  18,20-ethano-5-cis, 13-                                                       trans-prostadienoic acid                                371     292           9α,15-dihydroxy-4-nor-                                                  18,20-(1,3-propano)-                                                          5-cis,13-trans-prosta-                                                        dienoic acid                                            372     293           9α,15-dihydroxy-4-nor-                                                  16,20-methano-5-cis,13-                                                       trans,17-prostatrienoic                                                       acid                                                    373     294           9α,15-dihydroxy-4a-                                                     homo-17,20-methano-5-                                                         cis,13-trans-prosta-                                                          dienoic acid                                            374     295           9α,15-dihydroxy-4a-                                                     homo-16,17,18,19,20-                                                          pentanor-15(1-adaman-                                                         tyl)-5-cis,13-trans-                                                          prostadienoic acid                                      375     296           9α,15-dihydroxy-4a-                                                     homo-16,20-methano-5-                                                         cis,13-trans-prosta-                                                          dienoic acid                                            375a    103           9α,15-epi-dihydroxy-17,                                                 20-methano-13-trans-                                                          prostenoic acid                                         376     297           9α,15-dihydroxy-18,20-                                                  ethano-5-cis,13-trans-                                                        prostadienoic acid                                      377     298           9α,15-dihydroxy-20,20-                                                  (1,4-butano)-5-cis,13-                                                        trans-prostadienoic                                                           acid                                                    378     299           9α,15-dihydroxy-20-                                                     cyclopentyl-5-cis,13-                                                         trans-prostadienoic acid                                379     300           9α,15-dihydroxy-16-                                                     ethyl-19,20-(1,3-prop-                                                        ano)-5-cis,13-trans-                                                          prostadienoic acid                                      380     301           9α,15-dihydroxy-17,20- -  ethano-5-cis,13-tran                          s-                                                                            prostadienoic acid                                      381     302           9α,15-dihydroxy-19,20- -  (1,4-butano)-5-cis,1                          3-                                                                            trans-prostadienoic                                                           acid                                                    382     303           9α,15-dihydroxy-17,20-                                                  (1,3-propano)-5-cis,13-                                                       trans-prostadienoic                                                           acid                                                    383     304           9α,15-dihydroxy-20-                                                     methyl-17,20-ethano-5-                                                        cis,13-trans-prosta-                                                          dienoic acid                                            384     305           9α,15-dihydroxy-17,18,-                                                 19,20-tetranor-16-(1-                                                         adamantyl)-5-cis,13-                                                          trans-prostadienoic                                                           acid                                                    385     306           9α,15-dihydroxy-17- -  methyl-20-nor-16,18-                             ethano-5-cis,13-trans-                                                        prostadienoic acid                                      386     307           9α,15-dihydroxy-16,20-                                                  methano-5-cis,13-trans-                                                       prostadienoic acid                                      387     308           9α,15-dihydroxy-17,20-                                                  methano-5-cis,13-trans-                                                       prostadienoic acid                                      388     309           9α,15-dihydroxy-16,19-                                                  ethano-5-cis,13-trans-                                                        prostadienoic acid                                      389     310           9α,15-dihydroxy-16,20-                                                  (1,3-propano)-5-cis,13-                                                       trans-prostadienoic acid                                390     311           9α,15-dihydroxy-16,20-                                                  ethano-5-cis,13-trans-                                                        prostadienoic acid                                      391     312           9α,15-dihydroxy-16,17-                                                  18,19,20-pentanor-15-(1-                                                      adamantyl)-5-cis,13-                                                          trans-prostenoic acid                                   392     313           9α,15-dihydroxy-16,17,-                                                 18,19,20-pentanor-15-                                                         (2-adamantyl-5-cis,13-                                                        trans-prostadienoic acid                                393     314           9α,15-dihydroxy-16-                                                     methyl-16,20-methano-                                                         5-cis,13-trans-prosta-                                                        dienoic acid                                            394     315           9α,15-dihydroxy-17,20-                                                  methano-5-cis,13-trans-                                                       18-prostatrienoic acid                                  395     316           9α,15-dihydroxy-17,20-                                                  ethano-5-cis,13-trans-                                                        18-prostatrienoic acid                                  396     317           9α,15-dihydroxy-17,20-                                                  ethano-5-cis,13-trans-                                                        19-prostatrienoic acid                                  397     318           9α,15-dihydroxy-16,20-                                                  methano-5-cis,13-trans-                                                       17-prostatrienoic acid                                  398     319           9α,15-dihydroxy-16,20-                                                  methanao-5-cis,13-trans-                                                      18-prostatrienoic acid                                  399     320           9α,15-dihydroxy-4a,4b- -  bishomo-17-methyl-17                          ,-                                                                            20-methano-5-cis,13-                                                          trans-prostadienoic                                                           acid                                                    400     321           9α,15-dihydroxy-4a,4b-                                                  bishomo-18-methyl-17,20-                                                      methano-5-cis,13-trans-                                                       prostadienoic acid                                      401     322           9α,15-dihydroxy-4a,4b-                                                  bishomo-16,20-ethano-5-                                                       cis,13-trans-prosta-                                                          dienoic acid                                            402     323           9α,15-dihydroxy-4a,4b-                                                  bishomo-17,19-(1,3-                                                           propano)-5-cis,13-trans-                                                      prostadienoic acid                                      403     324           9α,15-dihydroxy-4a,4b-                                                  bishomo-16,19-ethano-5-                                                       cis,13-trans-prosta-                                                          dienoic acid                                            ______________________________________                                    

EXAMPLE 404 Preparation of9α/9β,15-dihydroxy-16,19-methano-20-nor-13-trans-prostenoic acid

To a stirred, ice-cold solution of 355 mg. (1.00 mmoles) of9-oxo-15-hydroxy-16,19-methano-20-nor-13-trans-prostenoic acid (Example166) in 50 ml. of ethanol is added 409 mg. (10.8 mmoles) of sodiumborohydride in small portions during 1 minute. The mixture is protectedfrom moisture and is stirred at 0° C. for 5 minutes and at ambienttemperature for 6 hours. The bulk of the ethanol is evaporated at roomtemperature, and the residue is treated with ether followed by dilutehydrochloric acid while cooling in an ice bath. The organic phase isseparated and washed with water and saturated sodium chloride solution.The solution is dried over magnesium sulfate and concentrated. Theresidue is purified by preparative thin layer chromatography on silicagel to give an oil, max 3310 (hydroxyl groups), 1705 (acid carbonylgroup), and 970 cm⁻¹ (trans vinyl group).

EXAMPLE 405-411

Treatment of the 9-oxo derivatives listed in Table 10 below with sodiumborohydride in accordance with the procedure described in Example 404 isproductive of the 9-hydroxy derivatives of the table. Each of thesederivatives represents a mixture of 9α- and 9β-hydroxy compounds.

                  Table 10                                                        ______________________________________                                                Starting                                                                      9-oxo-13-trans-                                                                             Product 9α/β,-                               Ex-     prostenoic    15-dihydroxy-13-                                        ample   acid of Example                                                                             trans-prostenoic acids                                  ______________________________________                                        405     251           9α/β,15-dihydroxy-17,20-                                           ethano-3-trans-prosten-                                                       oic acid                                                406     253           9α/β,15-dihydroxy-17,20-                                           ethano-20-methyl-13-                                                          trans-prostenoic acid                                   407     256           9α/β,15-dihydroxy-16,19-                                           ethano-20-methyl-13-                                                          trans-prostenoic acid                                   408     261           9α/β,15-dihydroxy-16,20-                                           methano-13-trans,17-                                                          prostadienoic acid                                      409     262           9α/β,15-dihydroxy-16,20-                                           methano-13-trans,18-                                                          prostadienoic acid                                      410     267           9α/β,15-dihydroxy-7a,                                              7b-bishomo-16,19-eth-                                                         ano-13-trans-prostenoic                                                       acid                                                    411     314           9α/β,15-dihydroxy-16-                                              methyl-16,20-methano-                                                         5-cis,13-trans-                                                               prostadienoic acid                                      ______________________________________                                    

EXAMPLE 412 Preparation of9-oxo-15-hydroxy-15-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoicacid and9α,15-dihydroxy-15-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoicacid

A solution of methyl9-oxo-15-hydroxy-20,20(1,4-butano)-5-cis,13-trans-prostadienoate(Example 220) in tetrahydrofuran is added to 1.1 equivalent of lithiumperhydro-9b-boraphenalyl hydride in tetrahydrofuran at -78° C. After 30minutes equal volumes of 5% aqueous sodium carbonate and 30% aqueoushydrogen peroxide is added, and the solution is stirred 15 minutes. Thesolution is diluted with water and extracted with ether. The organicphase is dried (magnesium sulfate) and concentrated in vacuo to givemethyl 9α,15-dihydroxy-20,20-(1,4-butano)-5-cis,13-trans-prostadienoate,contaminated with methyl 9β,15α-dihydroxy-5-cis,13-trans,17-cis-prostatienoate. The crude mixture ofesters is dissolved in methylene chloride and added to a refluxingsolution of 1.2 equivalents of 2,3-dichloro-5,6-dicyanobenzoquinone(DDQ) in methylene chloride. After 5 hours, the solution is cooled andfiltered. The filtrate is diluted with two volumes of ether, extractedwith 5% aqueous sodium carbonate and dried with magnesium sulfate. Thesolution is concentrated in vacuo to give methyl9α-hydroxy-15-oxo-20,20-(1,4-butano-5-cis-13-trans-prostadienoate and9β-hydroxy-15-oxo-20,20-(1,4-butano-5-cis,13-trans-prostadienoate. Thecrude material is dissolved in benzene and 1.2 equivalents each oftriethylamine and trimethylsilyl chloride is added. The triethylaminehydrochloride is removed by filtration and the solution is concentratedin vacuo to give methyl9α-trimethylsiloxy-15-oxo-20,20-(1,4-butano)-5-cis,13-trans-prostadienoateand the corresponding 9β-trimethylsiloxy derivative.

The siloxy derivatives are dissolved in ether at 0° C. and 1.05equivalents of methyl magnesium bromide in ether is added. After thereaction is complete, the solution is poured into saturated aqueousammonium chloride and extracted with ether. The ether is dried andconcentrated in vacuo to give methyl9α-trimethylsiloxy-15α-hydroxy-15β-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoate,and methyl9α-trimethylsiloxy-15β-hydroxy-15α-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoate,methyl9β-trimethylsiloxy-15α-hydroxy-15β-methyl-20,20-(1,4-butano-5-cis,13-trans-prostadienoate,and methyl9β-trimethylsiloxy-15β-hydroxy-15α-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoate.Hydrolysis of the siloxy functions of each in a solution of methanolwater and acetic and gives methyl9α,15α-dihydroxy-15β-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoate,methyl9α,15β-dihydroxy-15α-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoate,methyl9β,15α-dihydroxy-15β-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoateand methyl9β15β-dihydroxy-15α-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoate,which are separated by dry column chromatography and further purified bypartition chromatography. Saponification (method of Example 102) of eachcomponent in 50% aqueous methanol with potassium hydroxide gives thecorresponding free acids.

Treatment of a solution of methyl9α,15α-dihydroxy-15β-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoatein methylene chloride with Collins reagent gives methyl9-oxo-15α-hydroxy-15β-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoate,saponification of which (method of Example 102) gives9-oxo-15α-hydroxy-15β-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoicacid.

Similar treatment of the 15β-hydroxy esters gives methyl9-oxo-15β-hydroxy-15α-methyl-20,20-(1,4-butano)-5-cis-13-trans-prostadienoatewhich gives9-oxo-15β-hydroxy-15α-methyl-20,20-(1,4-butano)-5-cis,13-trans-prostadienoicacid after saponification.

EXAMPLES 413-446P

Treatment of the 9-oxo-15-hydroxy prostenoic esters of Table 11 below bythe sequence of reactions described in Example 412 is productive of the9α,15-dihydroxy-15-methyl and the 9-oxo-15-hydroxy-15-methyl products ofthe table. Also prepared in the course of these reaction sequences arethe ethyl or methyl esters corresponding to the products of the table,the 9β-hydroxy derivatives corresponding to the listed 9α-hydroxyderivatives and their ethyl or methyl esters, the 15-keto derivatives ofthe 9α- and 9β-hydroxy compounds corresponding to the 9-oxo startingcompounds, and the 9α- or 9β-trimethyl-silyloxy ethyl esters of the15-keto and 15-hydroxy-15-methyl compounds. In all cases both the15α-hydroxy-15β-methyl and the 15β-hydroxy-15α-methyl products andintermediates are obtained. These are separable by chromatographicprocedures.

                                      TABLE II                                    __________________________________________________________________________        Starting 9-oxo-15-                                                        Ex- hydroxy-13-trans-                                                         ample                                                                             prostenoate of Example                                                                    Product 15-hydroxy-15-methyl derivatives                      __________________________________________________________________________    413 167         9-oxo-15-hydroxy-15-methyl-18,20-ethano-13-trans-prostenoi                    c acid and                                                                    9α,15-dihydroxy-15-methyl-18,20-ethano-13-trans-pros                    tenoic acid                                                   414 168         9-oxo-15-hydroxy-15-methyl-19,20-(1,3-propano)-13-trans-pr                    ostenoic acid                                                                 and 9α,15-dihydroxy-15-methyl-19,20-(1,3-propano)-13                    -trans-prostenoic                                                             acid                                                          415 170         9-oxo-15-hydroxy-15-methyl-17,20-ethano-13-trans-prostenoi                    c acid and                                                                    9α,15-dihydroxy-15-methyl-17,20-ethano-13-trans-pros                    tenoic acid                                                   416 171         9-oxo-15-hydroxy-15-methyl-17,20-(1,3-propano)-13-trans-pr                    ostenoic acid                                                                 and 9α,15-dihydroxy-15-methyl-17,20-(1,3-propano)-13                    -trans-prostenoic                                                             acid                                                          417 172         9-oxo-15-hydroxy-15-methyl-17,20-ethano-20-methyl-13-trans                    -prostenoic                                                                   acid and 9α,15-dihydroxy-15-methyl-17,20-ethano-20-m                    ethyl-13-trans-                                                               prostenoic acid                                               418 175         9-oxo-15-hydroxy-15-methyl-16,20-methano-13-trans-prosteno                    ic acid and                                                                   9α,15-dihydroxy-15-methyl-16,20-methano-13-trans-pro                    stenoic acid                                                  419 178         9-oxo-15-hydroxy-15-methyl-17,20-methano-13-trans,18-prost                    adienoic acid                                                                 and 9α,15-dihydroxy-15-methyl-17,20-methano-13-trans                    ,18-prostadienoic                                                             acid                                                          420 179         9-oxo-15-hydroxy-15-methyl-17,20-ethano-13-trans,18-prosta                    dienoic acid                                                                  and 9α,15-dihydroxy-15-methyl-17,20-ethano-13-trans,                    18-prostadienoic                                                              acid                                                          421 180         9-oxo-15-hydroxy-15-methyl-17,20-ethano-13-trans,19-prosta                    dienoic acid                                                                  and 9α,15-dihydroxy-15-methyl-17,20-ethano-13-trans,                    19-prostadienoic                                                              acid                                                          422 184         9-oxo-5,6,7-trinor-15-hydroxy-15-methyl-20,20-(1,4-butano)                    -13-trans-                                                                    prostenoic acid and 5,6,7-trinor-9α,15-dihydroxy-15-                    methyl-20,20-(1-)                                                             butano)-13-trans-prostenoic acid                              423 185         9-oxo-6,7-dinor-15-hydroxy-15-methyl-20-cyclopentyl-13-tra                    ns-prostenoic                                                                 acid and 6,7-dinor-9α  ,15-dihydroxy-15-methyl-20-cy                    clopentyl-13-trans-                                                           prostenoic acid                                               424 186         9-oxo-7a,7b-bishomo-15-hydroxy-15-methyl-18-methyl-17,20-m                    ethano-13-                                                                    trans-prostenoic acid and 7a,7b-bishomo-9α,15-dihydr                    oxy-15-methyl-18-                                                             methyl)-17,20-ethano-13-trans-prostenoic acid                 425 188         9-oxo-10a-homo-15-hydroxy-15-methyl-17,19-(1,3-propano)-13                    -trans-pros-                                                                  tenoic acid and 10a-homo-9α,15-dihydroxy-15-methyl-1                    7,19-(1,3-propano-                                                            13-trans-prostenoic acid                                      426 190         9-oxo-2-ethyl-15-hydroxy-15-methyl-17,20-ethano-13-trans-p                    rostenoic                                                                     acid and 2-ethyl-9α,15-dihydroxy-15-methyl-17,20-eth                    ano-13-trans-                                                                 prostenoic acid                                               427 191         9-oxo-2-ethyl-15-hydroxy-15-methyl-17,20-methano-13-trans,                    18-prosta-                                                                    dienoic acid and 2-ethyl-9α,15-dihydroxy-15-methyl-1                    7,20-methano-13-                                                              trans,18-prostadienoic acid                                   428 194         9-oxo-2-methyl-15-hydroxy-15-methyl-17,19-methano-20-nor-1                    3-trans-                                                                      prostenoic acid and 2-methyl-9α,15-dihydroxy-15-meth                    yl-17,20-metha-                                                               20-nor-13-trans-prostenoic acid                               429 197         9-oxo-3,3-dimethyl-15-hydroxy-15-methyl-17,20-(1,4-butano)                    -13-trans-                                                                    prostenoic acid and 3,3-dimethyl-9α,15-dihydroxy-15-                    methyl-17,20-                                                                 (1,4-butano)-13-trans-prostenoic acid                         430 201         9-oxo-3-oxa-15-hydroxy-15-methyl-20-methyl-19,20-(1,3-prop                    ano)-13-                                                                      trans-prostenoic acid and 3-oxa-9α,15-dihydroxy-15-m                    ethyl-20-methyl-                                                              19,20-(1,3-propano)-13-trans-prostenoic acid                  431 203         9-oxo-3-oxa-15-hyrdroxy-15-methyl-17,20-ethano-13-trans,19                    -prosta-                                                                      dienoic acid and 3-oxa-9α,15-dihydroxy-15-methyl-17,                    20-ethano-13-                                                                 trans,19-prostadienoic acid                                   432 207         9-oxo-3-thia-15-hydroxy-15-methyl-17,20-ethano-13-trans-pr                    ostenoic                                                                      acid and 3-thia-9α,15-dihydroxy-15-methyl-17,20-etha                    no-13-trans-                                                                  prostenoic acid                                               433 208         9-oxo-2-fluoro-15-hydroxy-15-methyl-20-methyl-17,20-(1,3-p                    ropano)-15-                                                                   trans-prostenoic acid and 2-fluoro-9α,15-dihydroxy-1                    5-methyl-20-methyl-                                                           17,20-(1,3-propano)-13-trans-prostenoic acid                  434 213         9-oxo-15-hydroxy-15-methyl-4-nor-18,20-ethano-5-cis,13-tra                    ns-prosta-                                                                    dienoic acid and 9α,15-dihydroxy-15-methyl-4-nor-18,                    20-ethano-5-cis,-                                                             13-trans-prostadienoic acid                                   435 214         9-oxo-15-hydroxy-15-methyl-4-nor-18,20-(1,3-propano)-5-cis                    ,13-trans-                                                                    prostadienoic acid and 9α,15-dihydroxy-15-methyl-4-n                    or-18,20-(1,3-                                                                propano)-5-cis,13-trans-prostadienoic acid                    436 216         9-oxo-15-hydroxy-15-methyl-4a-homo-17,20-methano-5-cis,13-                    trans-prost-                                                                  dienoic acid and 9α,15-dihydroxy-15-methyl-4a-homo-1                    7,20-methano-5-cis,-                                                          13-trans-prostadienoic acid                                   437 219         9-oxo-15-hydroxy-15-methyl-18,20-ethano-5-cis,13-trans-pro                    stadienoic                                                                    acid and 9α,15-dihydroxy-15-methyl-18,20-ethano-5-ci                    s,13-trans-prosta-                                                            dienoic acid                                                  438 221         9-oxo-15-hydroxy-15-methyl-20-cyclopentyl-5-cis,13-trans-p                    rostadienoic                                                                  acid and 9α,15-dihydroxy-15-methyl-20-cyclopentyl-5-                    cis,13-trans-                                                                 prostadienoic acid                                            439 224         9-oxo-15-hydroxy-15-methyl-19,20-(1,4-butano)-5-cis,13-tra                    ns-prostadi-                                                                  enoic acid and 9α,15-dihydroxy-15-methyl-19,20-(1,4-                    butano)-5-cis,13-                                                             trans-prostadienoic acid                                      440 226         9-oxo-15-hydroxy-15-methyl-20-methyl-17,20-ethano-5-cis,13                    -trans-                                                                       prostadienoic acid and 9α,15-dihydroxy-15-methyl-20-                    methyl-17,20-                                                                 ethano-5-cis,13-trans-prostadienoic acid                      441 230         9-oxo-15-hydroxy-15-methyl-17,20-methano-5-cis,13-trans-pr                    ostadi-                                                                       enoic acid and 9α,15-dihydroxy-15-methyl-17,20-metha                    no-5-cis,13-                                                                  trans-prostadienoic acid                                      442 237         9-oxo-15-hydroxy-15-methyl-17,20-methano-5-cis,13-trans,18                    -prosta-                                                                      trienoic acid and 9α,15-dihydroxy-15-methyl-17,20-me                    thano-5-cis,13-                                                               trans,18-prostatrienoic acid                                  443 238         9-oxo-15-hydroxy-15-methyl-17,20-ethano-5-cis,13-trans,18-                    prostatrien-                                                                  oic acid and 9α,15-dihydroxy-15-methyl-17,20-ethano-                    5-cis,13-trans,18-                                                            prostatrienoic acid                                           444 239         9-oxo-15-hydroxy-15-methyl-17,20-ethano-5-cis,13-trans,19-                    prostatrien-                                                                  oic acid and 9α,15-dihydroxy-15-methyl-17,20-ethano-                    5-cis,13-trans,19-                                                            prostatrienoic acid                                           445 243         9-oxo-15-hydroxy-15-methyl-4a,4b-bishomo-18-methyl-17,20-m                    ethano-5-cis,-                                                                13-trans-prostadienoic acid and 9α,15-dihydroxy-15-m                    ethyl-4a,4b-bis-                                                              homo-18-methyl-17,20-methano-5-cis,13-trans-prostadienoic                     acid                                                          446 245         9-oxo-15-hydroxy-15-methyl-4a,4b-bishomo-17,19-(1,3-propan                    o)-5-cis-13-                                                                  trans-prostadienoic acid and 9α,15-dihydroxy-15-meth                    yl-4a,4b-bishomo-                                                             17,19-(1,3-propano)-5-cis,13-trans-prostadienoic acid         446A                                                                              544         9-oxo-15-hydroxy-15-methyl-cis-17,18-methano-13-trans-pros                    tenoic acid                                                                   and 9α,15-dihydroxy-15-methyl-cis-17,18-methano-13-t                    rans-prostenoic acid                                          446B                                                                              546         9-oxo-6,7-dinor-15-hydroxy-15-methyl-cis-17,18-methano-13-                    trans-pros-                                                                   tenoic acid and 9α,15-dihydroxy-6,7-dinor-15-methyl-                    cis,17,18-meth-                                                               ano-13-trans-prostenoic acid                                  446C                                                                              547         9-oxo-7a,7b-bishomo-15-hydroxy-15-methyl-cis-17,18-methano                    -13-trans-                                                                    prostenoic acid and 9α,15-dihydroxy-7a,7b-bishomo-15                    -methyl-cis,17,18-                                                            methano-13-trans-prostenoic acid                              446D                                                                              548         9-oxo-2-ethyl-15-hydroxy-15-methyl-cis-17,18-methano-13-tr                    ans-prosten-                                                                  oic acid and 9α,15-dihydroxy-2-ethyl-15-methyl-cis-1                    7,18-methano-13-                                                              trans-prostenoic acid                                         446E                                                                              549         9-oxo-10a-homo-15-hydroxy-15-methyl-cis-17,18-methano-13-t                    rans-pros-                                                                    tenoic acid and 9α,15-dihydroxy-10a-homo-15-methyl-c                    is-17,18-methano-                                                             13-trans-prostenoic acid                                      446F                                                                              550         9-oxo-2-methyl-15-hydroxy-15-methyl-cis-17,18-methano-13-t                    rans-pros-                                                                    tenoic acid and 9α,15-dihydroxy-2-methyl-15-methyl-c                    is-17,18-methano-                                                             13-trans-prostenoic acid                                      446G                                                                              551         9-oxo-3,3-dimethyl-15-hydroxy-15-methyl-cis-17,18-methano-                    13-trans-                                                                     prostenoic acid and 9α,15-dihydroxy-3,3-dimethyl-15-                    methyl-cis-17,18-                                                             methano-13-trans-prostenoic acid                              446H                                                                              552         9-oxo-3-oxa-15-hydroxy-15-methyl-cis-17,18-methano-13-tran                    s-prostenoic                                                                  acid and 9α,15-dihydroxy-3-oxa-15-methyl-cis-17,18-m                    ethano-13-trans-                                                              prostenoic acid                                               446I                                                                              553         9-oxo-3-thia-15-hydroxy-15-methyl-cis-17,18-methano-13-tra                    ns-prostenoic                                                                 acid and 9α,15-dihydroxy-3-thia-15-methyl-cis-17,18-                    methano-13-trans-                                                             prostenoic acid                                               446J                                                                              554         9-oxo-2-fluoro-15-hydroxy-15-methyl-cis,17,18-methano-13-t                    rans-pros-                                                                    tenoic acid and 9α,15-dihydroxy-2-fluoro-15-methyl-c                    is-17,18-methano-                                                             13-trans-prostenoic acid                                      446K                                                                              555         9-oxo-2-phenyl-15-hydroxy-15-methyl-cis-17,18-methano-13-t                    rans-pros-                                                                    tenoic acid and 9α,15-dihydroxy-2-phenyl-15-methyl-c                    is-17,18-methano-                                                             13-trans-prostenoic acid                                      446L                                                                              558         9-oxo-4-nor-15-hydroxy-15-methyl-cis-17,18-methano-5-cis,1                    3-trans-                                                                      prostadienoic acid and 9α,15-dihydroxy-4-nor-15-meth                    yl-cis-17,18-                                                                 methano-5-cis,13-trans-prostadienoic acid                     446M                                                                              559         9-oxo-4a-homo-15-hydroxy-15-methyl-cis-17,18-methano-5-cis                    ,13-trans-                                                                    prostadienoic acid and 9α,15-dihydroxy-4a-homo-15-me                    thyl-cis-17,18-                                                               methano-5-cis,13-trans-prostadienoic acid                     446N                                                                              560         9-oxo-15-hydroxy-15-methyl-cis-17,18-methano-5-cis,13-tran                    s-prosta-                                                                     dienoic acid and 9α,15-dihydroxy-15-methyl-cis-17,18                    -methano-5-cis,13-                                                            trans-prostadienoic acid                                      446P                                                                              561         9-oxo-4a,4b-bishomo-15-hydroxy-15-methyl-cis-17,18-methano                    -5-cis,13-                                                                    trans-prostadienoic acid and 9α,15-dihydroxy-4a,4b-b                    ishomo-15-methyl-                                                             cis-17,18-methano-5-cis,13-trans-prostadienoic                __________________________________________________________________________                    acid                                                      

EXAMPLE 447 Preparation of 9-oxo-15-hydroxy-17,21-methanoprostanoic acid

A 2 g. sample of 9-oxo-15-hydroxy-17,20-methano-13-trans-prostenoic acid(Example 102) is hydrogenated using 700 mg. of 10% palladium on carbonin 50 ml. of absolute alcohol. The catalyst is removed by filtration andthe mother liquor is taken to dryness to give 2 g. of subject compoundas an oil.

EXAMPLES 448-512

Catalytic hydrogenation with 10% palladium-on-carbon catalyst by theprocedure described in Example 447 of the various prostenoic acids oresters listed below in Table 12 provides the corresponding productprostenoic acids or esters of the table.

                  TABLE 12                                                        ______________________________________                                                Starting proste-                                                      Exam-   noic acid or  Product 15-hydroxy-pro-                                 ple     ester of example                                                                            stanoic acid or ester                                   ______________________________________                                        448     247           9-oxo-15-hydroxy-16,19-                                                       methano-20-nor-prosta-                                                        noic acid                                               449     248           9-oxo-15-hydroxy-18,20-                                                       ethano-prostanoic acid                                  450     249           9-oxo-15-hydroxy-19,20-                                                       (1,3-propano)-prosta-                                                         noic acid                                               451     250           9-oxo-15-hydroxy-16-                                                          methyl-18,20-ethano-                                                          prostanoic acid                                         452     251           9-oxo-15-hydroxy-17,20-                                                       ethano-prostanoic acid                                  453     252           9-oxo-15-hydroxy-17,20-                                                       (1,3-propano)-prosta-                                                         noic acid                                               454     253           9-oxo-15-hydroxy-17,20-                                                       ethano-20-methyl-pro-                                                         stanoic acid                                            455     254           9-oxo-15-hydroxy-17,18-                                                       19,20-tetranor-16-(1-                                                         adamantyl)-prostanoic                                                         acid                                                    456     255           9-oxo-15-hydroxy-16,20-                                                       methano-prostanoic                                                            acid                                                    457     256           9-oxo-15-hydroxy-16,19-                                                       ethano-prostanoic acid                                  458     257           9-oxo-15-hydroxy-16,20-                                                       (1,3-propano)-prosta-                                                         noic acid                                               459     263           9-oxo-15-hydroxy-16,17,-                                                      18,19,20-pentanor-15-                                                         (1-adamantyl)-prosta-                                                         noic acid                                               460     264           9-oxo-5,6,7-trinor-15-                                                        hydroxy-20,20-(1,4-                                                           butano)-prostanoic                                                            acid                                                    461     265           9-oxo-6,7-dinor-15-hy-                                                        droxy-20-cyclopentyl-                                                         prostanoic acid                                         462     266           9-oxo-7a,7b-bishomo-15-                                                       hydroxy-18-methyl-17,-                                                        20-methano-prostanoic                                                         acid                                                    463     267           9-oxo-7a,7b-bishomo-15-                                                       hydroxy-16,19-ethano-                                                         prostanoic acid                                         464     268           9-oxo-10a-homo-15-hy-                                                         droxy-17,19-(1,3-pro-                                                         pano)-prostanoic acid                                   465     269           9-oxo-10a-homo-15-hy-                                                         droxy-17,18,19,20-te-                                                         tranor-16-(1-adamantyl)-                                                      prostanoic acid                                         466     270           9-oxo-2-ethyl-15-hydro-                                                       xy-17,20-ethano-prosta-                                                       noic acid                                               467     273           9-oxo-2-methyl-15-hy-                                                         droxy-16-ethyl-19,20-                                                         (1,3-propano)-prosta-                                                         noic acid                                               468     274           9-oxo-2-methyl-15-hy-                                                         droxy-17,19-methano-20-                                                       nor-prostanoic acid                                     469     275           9-oxo-2-methyl-15-hy-                                                         droxy-16,20-(1,3-pro-                                                         pano)-prostanoic acid                                   470     276           9-oxo-3,3-dimethyl-15-                                                        hydroxy-16,20-methano-                                                        prostanoic acid                                         471     277           9-oxo-3,3-dimethyl-15-                                                        hydroxy-17,20-(1,4-bu-                                                        tano)-prostanoic acid                                   472     279           9-oxo-3-oxa-15-hydroxy-                                                       16,19-ethano-prosta-                                                          noic acid                                               473     280           9-oxo-3-oxa-15-hydroxy-                                                       17,18,19,20-tetranor-                                                         16-(1-adamantyl)-pro-                                                         stanoic acid                                            474     281           9-oxo-3-oxa-15-hydroxy-                                                       20-methyl-19,20-(1,3-                                                         propano)-prostanoic                                                           acid                                                    475     282           9-oxo-3-oxa-15-hydroxy-                                                       16-ethyl-19,20-(1,3-                                                          propano)-prostanoic                                                           acid                                                    476     288           9-oxo-2-fluoro-15-hy-                                                         droxy-20-methyl-17,20-                                                        (1,3-propano)-prosta-                                                         noic acid                                               477     289           9-oxo-2-fluoro-15-hy-                                                         droxy-16,17,18,19,20-                                                         pentanor-15-(2-adaman-                                                        tyl)-prostanoic acid                                    478     290           9-oxo-2-phenyl-15-hy-                                                         droxy-16,20-methano-                                                          prostanoic acid                                         479     174           decyl 9-oxo-15-hydroxy-                                                       20-nor-16,19-methano-                                                         prostanoate                                             480     211           butyl 9-oxo-15-hydroxy-                                                       16,20-ethanoprostano-                                                         ate                                                     481     199           ethyl 9-oxo-3-oxa-15-                                                         hydroxy-16,19-ethano-                                                         prostanoate                                              481a   103           9-oxo-15-epi-hydroxy-                                                         17,20-methano-prosta-                                                         noate                                                   482     326           9α,15-dihydroxy-16,19-                                                  methano-20-nor-prosta-                                                        noic acid                                               483     327           9α,15-dihydroxy-18,20-                                                  ethano-prostanoic acid                                  497     347           10a-homo-9α,15-dihydro-                                                 xy-17,19-(1,3-propano)-                                                       prostanoic acid                                         498     348           10a-homo-9α,15-dihydro-                                                 xy-17,18,19,20-tetra-                                                         nor-16-(1-adamantyl)-                                                         prostanoic acid                                         499     349           2-ethyl-9α,15-dihydro-                                                  xy-17,20-ethano-prosta-                                                       noic acid                                               500     352           2-methyl-9α,15-dihydro-                                                 xy-16-ethyl-19,20-(1,3-                                                       propano)-prostanoic                                                           acid                                                    501     353           2-methyl-9α,15-dihydro-                                                 xy-17,19-methano-20-                                                          nor-prostanoic acid                                     502     354           2-methyl-9α,15-dihydro-                                                 xy-16,20-(1,3-propano)-                                                       prostanoic acid                                         503     355           3,3-dimethyl-9α,15-di-                                                  hydroxy-16,20-methano-                                                        prostanoic acid                                         504     356           3,3-dimethyl-9α,15-di-                                                  hydroxy-17,20-(1,4-bu-                                                        tano)-prostanoic acid                                   505     358           3-oxa-9α,15-dihydroxy-                                                  16,19-ethano-prosta-                                                          noic acid                                               506     359           3-oxa-9α,15-dihydroxy-                                                  17,18,19,20-tetranor-                                                         16-(1-adamantyl)-pro-                                                         stanoic acid                                            507     360           3-oxa-9α,15-dihydroxy-                                                  20-methyl-19,20-(1,3-                                                         propano)-prostanoic                                                           acid                                                    508     361           3-oxa-9α,15-dihydroxy-                                                  16-ethyl-19,20-(1,3-                                                          propano)-prostanoic                                                           acid                                                    509     325           9α,15-dihydroxy-17,20-                                                  methano-prostanoic                                                            acid                                                    510      413*         9-oxo-15-hydroxy-15-                                                          methyl-18,20-ethano-                                                          prostanoic acid                                         511      414*         9-oxo-15-hydroxy-15-                                                          methyl-19,20-(1,3-pro-                                                        pano)-prostanoic acid                                   512      430*         9-oxo-3-oxa-15-hydroxy-                                                       15-methyl-19,20-(1,3-                                                         propano)-prostanoic                                                           acid                                                     512a    375a         9α,15-epi-dihydroxy-                                                    17,20-methano-prosta-                                                         noic acid                                               ______________________________________                                         *9-oxo product of this example.                                          

EXAMPLES 513-542

Treatment of the prostenoic or prostanoic acids listed in Table 13 belowwith the indicated diazoalkane in the following manner provides theproduct esters of the table.

An ethereal solution containing a molar excess of diazoalkane is addedto a solution of prostenoic acid in ether (or acetone). After two tofour hours the solution is carefully evaporated under reduced pressureand the residual ester is purified in the usual way by chromatography onsilica gel.

                                      TABLE 13                                    __________________________________________________________________________         Starting acid of                                                         Example                                                                            Example  Diazoalkane                                                                          Product Ester                                            __________________________________________________________________________    513  250      diazodecane                                                                          decyl 9-oxo-15-hydroxy-16-methyl-18,20-ethano-13-tran                         s-                                                                            prostenoate                                              514  256      diazoheptane                                                                         heptyl 9-oxo-15-hydroxy-16,19-ethano-13-trans-                                prostenoate                                              515  262      diazoheptane                                                                         heptyl 9-oxo-15-hydroxy-16,20-methano-13-trans,                               18-prostadienate                                         516  267      diazodecane                                                                          decyl 9-oxo-7α,7β-bishomo-16,19-ethano-13-                         trans-                                                                        prostenoate                                              517  282      diazopentane                                                                         pentyl 9-oxo-3-oxa-15-hydroxy-16-ethyl-19,20-(1,3-                            propano)-prostenoate                                     518  285      diazodecane                                                                          decyl 9-oxo-3-thia-15-hydroxy-16-methyl-18,20-ethano-                         prostenoate                                              519  296      diazodecane                                                                          decyl 9-oxo-4α-homo-15-hydroxy-16,20-methano-5-                         cis,                                                                          13-trans-prostadienoate                                  520  300      diazodecane                                                                          decyl 9-oxo-15-hydroxy-16-ethyl-19,20-(1,3-propanO)-                          5-cis,13-trans-prostadienoate                            521  309      diazoheptane                                                                         heptyl 9-oxo-15-hydroxy-16,19-ethano-5-cis,13-trans-                          prostadienoate                                           522  309      diazopentane                                                                         pentyl 9-oxo-15-hydroxy-16,19-ethano-5-cis,13-                                trans-prostadienoate                                     523  309      diazodecane                                                                          decyl 9-oxo-15-hydroxy-16,19-ethano-5-cis,13-                                 trans-prostadienoate                                     524  314      diazodecane                                                                          decyl 9-oxo-15-hydroxy-16-methyl-16,20-methano-                               5-cis,13-trans-prostadienoate                            525  335      diazodecane                                                                          decyl 9α,15-dihydroxy-16,19-ethano-13-trans-                            prostenoate                                              526  335      diazopentane                                                                         pentyl 9α,15-dihydroxy-16,19-ethano-13-trans-                           prostenoate                                              527  335      diazopentane                                                                         heptyl 9α,15-dihydroxy-16,19-ethano-13-trans-                           prostenoate                                              528  379      diazoheptane                                                                         heptyl 9α,15-dihydroxy-16-ethyl-19,20-(1,3-                             propano)-5-cis,13-trans-prostadienoate                   529  386      diazoheptane                                                                         heptyl 9α,15-dihydroxy-16,20-methano-5-cis,13-                          trans-prostadienoate                                     530  413      diazodecane                                                                          decyl 9-oxo-15-hydroxy-15-methyl-18,20-ethano-13-                             trans-prostenoate                                        531  414      diazodecane                                                                          decyl 9-oxo-15-hydroxy-15-methyl-19,20-(1,3-pro-                              pano-13-trans-prostenoate                                532  437      diazodecane                                                                          decyl 9-oxo-15-hydroxy-15-methyl-18,20-ethano-                                5-cis,13-trans-prostadienoate                            533  437      diazopentane                                                                         pentyl 9-oxo-15-hydroxy-15-methyl-18,20-ethano-5-                             cis,13-trans-prostadienoate                              534  437      diazoheptane                                                                         heptyl 9-oxo-15-hydroxy-15-methyl-18,20-ethano-5-                             cis,13-trans-prostadienoate                              535  439      diazoheptane                                                                         heptyl 9-oxo-15-hydroxy-15-methyl-19,20-(1,4-                                 butano)-5-cis,13-trans-prostadienoate                    535A 441      diazoheptane                                                                         heptyl 9-oxo-15-hydroxy-15-methyl-17,20-methano-                              5-cis,13-trans-prostadienoate                            536  457      diazodecane                                                                          decyl 9-oxo-15-hydroxy-16,19-ethano-prostanoate          537  448      diazoheptane                                                                         heptyl 9-oxo-15-hydroxy-16,19-methano-20-nor-                                 prostanoate                                              538  464      diazoheptane                                                                         heptyl 9-oxo-10a-homo-15-hydroxy-17,19-(1,3-pro-                              pano)-prostanoate                                        539  102      diazodecane                                                                          decyl 9-oxo-15-hydroxy-17,20-methano-13-trans-                                prostenoate                                              540  102      diazoheptane                                                                         heptyl 9-oxo-15-hydroxy-17,20-methano-13-trans-                               prostenoate                                              541  103      diazodecane                                                                          decyl 9-oxo-15-epi-hydroxy-17,20-methano-13-trans-                            prostenoate                                              542  103      diazoheptane                                                                         heptyl 9-oxo-15-epi-hydroxy-17,20-methano-13-                                 trans-prostenoate                                        __________________________________________________________________________

EXAMPLE 543

Treatment of 1-iodo-3-triphenylmethoxy-cis-5,6-methylene-trans-1-octene(Example 86) with butyl lithium by the procedure described in Example101 is productive of3-triphenylmethoxy-cis-5,6-methylene-trans-1-octenyl lithium, which ontreatment with trimethyl aluminum by the procedure described in Example101 furnisheslithio(3-triphenylmethoxy-cis-5,6-methylene-trans-1-octenyl)trimethylalanate.

EXAMPLES 544-561

Treatment of the cycloalkenone listed in Table 14 below withlithio(3-triphenylmethoxy-cis-5,6-methylene-trans-1-octenyl)trimethylalanate (Example 543) followed by acid-catalyzed de-O-tritylation of theintermediate alkyl 9-oxo-15-triphenylmethoxy-13-trans-prostenoate isproductive of the alkyl9-oxo-15-hydroxy-cis-17,18-methano-13-trans-prostenoates of the table.The entire sequence is carried out by the procedures described inExample 101.

                  TABLE 14                                                        ______________________________________                                                                Product alkyl 9-oxo-15-                                                       hydroxy-cis-17,18-                                    Ex-     Starting cyclo- methano-13-trans-                                     ample   alkenone        prostenoate                                           ______________________________________                                        544     2-(6-carbethoxy-                                                                              ethyl 9-oxo-15-hydroxy-                                       hexyl)cyclopent-                                                                              cis-17,18-methano-13-                                         2-en-1-one*     trans-prostenoate                                     545     2-(6-carbo-n-   decyl 9-oxo-15-hydroxy-                                       decyloxyhexyl)- cis-17,18-methano-13-                                         cyclopent-2-en- trans-prostenoate                                             1-one                                                                         (Example 7)                                                           546     2-(4-carbethoxy-                                                                              ethyl 9-oxo-6,7-dinor-                                        butyl)cyclopent-                                                                              15-hydroxy-cis-17,18-                                         2-en-1-one*     methano-13-trans-                                                             prostenoate                                           547     2-(8-carbethoxy-                                                                              ethyl 9-oxo-7a,7b-bis-                                        ocytl)cyclopent-                                                                              homo-15-hydroxy-cis-17,-                                      2-en-1-one*     18-methano-13-trans-                                                          prostenoate                                           548     2-(6-carbethoxy-                                                                              ethyl 9-oxo-2-ethyl-15-                                       octyl)cyclopent-                                                                              hydroxy-cis-17,18-                                            2-en-1-one*     methano-13-trans-                                                             prostenoate                                           549     2-(6-carbethoxy-                                                                              ethyl 9-oxo-10a-homo-                                         hexyl)cyclohex-2-                                                                             15-hydroxy-cis-17,18-                                         en-1-one*       methano-13-trans-                                                             prostenoate                                           550     2-(6-carbethoxy-                                                                              ethyl 9-oxo-2-methyl-                                         heptyl)cyclopent-                                                                             15-hydroxy-cis-17,18-                                         2-en-1-one      methano-13-trans-                                             (Example 3)     prostenoate                                           551     2-(6-carbethoxy-                                                                              ethyl 9-oxo-3,3-dimeth-                                       5,5-dimethyl-   yl-15-hydroxy-cis-17,-                                        hexyl)cyclopent-                                                                              18-methano-13-trans-                                          2-en-1-one*     prostenoate                                           552     2-(6-carbethoxy-                                                                              ethyl 9-oxo-3-oxa-15-                                         5-oxahexyl)cy-  hydroxy-cis-17,18-                                            clopent-2-en-1- methano-13-trans-                                             one*            prostenoate                                           553     2-(6-carbethoxy-                                                                              ethyl 9-oxo-3-thia-15-                                        5-thiahexyl)cy- hydroxy-cis-17,18-                                            clopent-2-en-1- methano-13-trans-                                             one*            prostenoate                                           554     2-(6-carbethoxy-                                                                              ethyl 9-oxo-2-fluoro-                                         6-fluorohexyl)- 15-hydroxy-cis-17,18-                                         cyclopent-2-en- methano-13-trans-                                             1-one (Exam-    prostenoate                                                   ple 1)                                                                555     2-(6-carbethoxy-                                                                              ethyl 9-oxo-2-phenyl-                                         6-phenylhexyl)- 15-hydroxy-cis-17,18-                                         cyclopent-2-en- methano-13-trans-                                             one (Example 2) prostenoate                                           556     2-(6-carbo-n-   butyl 9-oxo-15-hydroxy-                                       butoxyhexyl)cy- cis-17,18-methano-13-                                         clopent-2-en-1- trans-prostenoate                                             one (Example 4)                                                       557     2-(6-carboisopro-                                                                             isopropyl 9-oxo-15-hy-                                        poxyhexyl)cyclo-                                                                              droxy-cis-17,18-meth-                                         pent-2-en-1-one ano-13-trans-prosten-                                         (Example 5)     oate                                                  558     2-(5-carbometh- methyl 9-oxo-4-nor-15-                                        oxy-2-cis-pen-  hydroxy-cis-17,18-                                            tenyl)cyclopent-                                                                              methano-5-cis,13-trans-                                       2-en-1-one      prostadienoate                                                (Example 28)                                                          559     2-(7-carbometh- methyl 9-oxo-4a-homo-                                         oxy-2-cis-hep-  15-hydroxy-cis-17,18-                                         tenyl)cyclopent-                                                                              methano-5-cis,13-trans-                                       2-en-1-one      prostadienoate                                                (Example 29)                                                          560     2-(6-carbometh- methyl 9-oxo-15-hydroxy-                                      oxy-2-cis-hex-  cis-17,18-methano-5-                                          enyl)cyclopent- cis,13-trans-prosta-                                          2-en-1-one      dienoate                                                      (Example 14)                                                          561     2-(6-carbometh- methyl 9-oxo-4a,4b-bis-                                       oxy-2-cis-octen-                                                                              homo-15-hydroxy-cis-                                          yl)cyclopent-2- 17,18-methano-5-cis,-                                         en-1-one        13-trans-prostadienoate                                       (Example 30)                                                          ______________________________________                                         *Belgium Patent No. 786,215 (January 15, 1973).                          

EXAMPLES 562-576

Saponification by the procedure described in Example 102 of the alkylesters listed in Table 15 below provides the product9-oxo-15-hydroxy-cis-17,18-methano-13-trans-prostenoic acids of thetable.

                  TABLE 15                                                        ______________________________________                                                              Product 9-oxo-15-hy-                                           Starting Alkyl droxy-cis-17,18-methano-                                       Ester of       13-trans-prostenoic                                     Ex.    Example        acid                                                    ______________________________________                                        562    544            9-oxo-15-hydroxy-cis-                                                         17,18-methano-13-                                                             trans-prostenoic acid                                   563    546            9-oxo-6,7-dinor-15-hy-                                                        droxy-cis-17,18-methano-                                                      13-trans-prostenoic                                                           acid                                                    564    547            9-oxo-7a,7b-bishomo-15-                                                       hydroxy-cis-17,18-                                                            methano-13-trans-                                                             prostenoic acid                                         565    548            9-oxo-2-ethyl-15-hy-                                                          droxy-cis-17,18-methano-                                                      13-trans-prostenoic                                                           acid                                                    566    549            9-oxo-10a-homo-15-hy-                                                         droxy-cis-17,18-                                                              methano-13-trans-                                                             prostenoic acid                                         567    550            9-oxo-2-methyl-15-hy-                                                         droxy-cis-17,18-                                                              methano-13-trans-                                                             prostenoic acid                                         568    551            9-oxo-3,3-dimethyl-15-                                                        hydroxy-cis-17,18-                                                            methano-13-trans-                                                             prostenoic acid                                         569    552            9-oxo-3-oxa-15-hydroxy-                                                       cis-17,18-methano-13-                                                         trans-prostenoic acid                                   570    553            9-oxo-3-thia-15-hy-                                                           droxy-cis-17,18-meth-                                                         ano-13-trans-prostenoic                                                       acid                                                    571    554            9-oxo-2-fluoro-15-hy-                                                         droxy-cis-17,18-methano-                                                      13-trans-prostenoic                                                           acid                                                    572    555            9-oxo-2-phenyl-15-hy-                                                         droxy-cis-17,18-meth-                                                         ano-13-trans-pros-                                                            tenoic acid                                             573    558            9-oxo-4-nor-15-hydroxy-                                                       cis-17,18-methano-5-                                                          cis,13-trans-prosta-                                                          dienoic acid                                            574    559            9-oxo-4a-homo-15-hy-                                                          droxy-cis-17,18-meth-                                                         5-cis,13-trans-pros-                                                          tadienoic acid                                          575    560            9-oxo-15-hydroxy-cis-                                                         17,18-methano-5-cis,                                                          13-trans-prostadienoic                                                        acid                                                    576    561            9-oxo-4a,4b-bishomo-15-                                                       hydroxy-cis-17,18-                                                            methano-5-cis,13-                                                             trans-prostadienoic                                                           acid                                                    ______________________________________                                    

EXAMPLES 577-591

Treatment of the 9-oxo derivatives listed below in Table 16 with lithiumperhydro-9b-boraphenalyl hydride by the procedure described in Example325 provides the product 9α,15-dihydroxy-cis-17,18-methano-prostenoicacids of the table.

                  TABLE 10                                                        ______________________________________                                                 Starting                                                                      9-oxo                                                                         deriva-    Product 9α,15-dihydroxy-cis-17,                              tive of    18-methano-13-trans-prostenoic                            Example  Example    acid                                                      ______________________________________                                        577      562        9α,15-dihydroxy-cis-17,18-meth-                                         ano-13-trans-prostenoic acid                              578      563        9α,15-dihydroxy-6,7-dinor-cis-                                          17,18-methano-13-trans-pros-                                                  tenoic acid                                               579      564        9α,15-dihydroxy-7a,7b-bishomo-                                          cis-17,18-methano-13-trans-                                                   prostenoic acid                                           580      565        9α,15-dihydroxy-2-ethyl-cis-                                            17,18-methano-13-trans-pros-                                                  tenoic acid                                               581      566        9α,15-dihydroxy-10a-homo-cis-                                           17,18-methano-13-trans-pros-                                                  tenoic acid                                               582      567        9α,15-dihydroxy-2-methyl-cis-                                           17,18-methano-13-trans-pros-                                                  tenoic acid                                               583      568        9α,15-dihydroxy-3,3-dimethyl-                                           cis-17,18-methano-13-trans-                                                   prostenoic acid                                           584      569        9α,15-dihydroxy-3-oxa-cis-17,                                           18-methano-13-trans-prostenoic                                                acid                                                      585      570        9α,15-dihydroxy-3-thia-cis-17,                                          18-methano-13-trans-prostenoic                                                acid                                                      586      571        9α,15-dihydroxy-2-fluoro-cis-                                           17,18-methano-13-trans-pros-                                                  tenic acid                                                587      572        9α,15-dihydroxy-2-phenyl-cis-                                           17,18-methano-13-trans-pros-                                                  tenoic acid                                               588      573        9α,15-dihydroxy-4-nor-cis-17,                                           18-methano-5-cis,13-trans-pros-                                               tadienoic acid                                            589      574        9α,15-dihydroxy-4a-homo-cis-17,                                         18-methano-5-cis,13-trans-pros-                                               tadienoic acid                                            590      575        9α,15-dihydroxy-cis-17,18-meth-                                         ano-5-cis,13-trans-prostadienoic                                              acid                                                      591      576        9α,15-dihydroxy-4a,4b-bishomo-                                          cis-17,18-methano-5-cis,13-                                                   trans-prostadienoic acid                                  ______________________________________                                    

EXAMPLES 592-628

Hydrogenation of the 13-trans-prostenoic acids or esters listed in Table17 below in the presence of 10% palladium-on-carbon catalyst by theprocedure described in Example 447 furnishes the product prostanoic acidand ester of the table.

                  TABLE 17                                                        ______________________________________                                                Starting 13-                                                                  trans-prosten-                                                        Ex-     oic acid or ester                                                                            Product prostanoic acid                                ample   of Example     or ester                                               ______________________________________                                        592     544            ethyl 9-oxo-15-hydroxy-                                                       cis-17,18-methano-                                                            prostanoate                                            593     545            decyl 9-oxo-15-hydroxy-                                                       cis-17,18-methano-                                                            prostanoate                                            594     563            9-oxo-6,7-dinor-15-hy-                                                        droxy-cis-17,18-meth-                                                         ano-prostanoic acid                                    595     564            9-oxo-7a,7b-bishomo-15-                                                       hydroxy-cis-17,18-                                                            methano-prostanoic                                                            acid                                                   596     565            9-oxo-2-ethyl-15-hy-                                                          droxy-cis-17,18-meth-                                                         ano-prostanoic acid                                    597     566            9-oxo-10a-homo-15-hy-                                                         droxy-cis-17,18-meth-                                                         ano-prostanoic acid                                    598     567            9-oxo-2-methyl-15-hy-                                                         droxy-cis-17,18-meth-                                                         ano-prostanoic acid                                    599     568            9-oxo-3,3-dimethyl-15-                                                        hydroxy-cis-17,18-                                                            methano-prostanoic                                                            acid                                                   600     569            9-oxo-3-oxa-15-hydroxy-                                                       cis-17,18-methano-                                                            prostanoic acid                                        601     570            9-oxo-3-thia-15-hydroxy-                                                      cis-17,18-methano-                                                            prostanoic acid                                        602     571            9-oxo-2-fluoro-15-hy-                                                         droxy-cis-17,18-methano-                                                      prostanoic acid                                        603     572            9-oxo-2-phenyl-15-hy-                                                         droxy-cis-17,18-methano-                                                      prostanoic acid                                        604     556            butyl 9-oxo-15-hydroxy-                                                       cis-17,18-methano-                                                            prostanoic acid                                        605     557            isopropyl 9-oxo-15-hy-                                                        droxy-cis-17,18-meth-                                                         ano-prostanoic acid                                    606     562            9-oxo-15-hydroxy-cis-                                                         17,18-methano-prostan-                                                        oic acid                                               607     577            9α,15-dihydroxy-cis-                                                    17,18-methano-prostan-                                                        oic acid                                               608     578            9α,15-dihydroxy-6,7-di-                                                 nor-cis-17,18-methano-                                                        prostanoic acid                                        609     579            9α,15-dihydroxy-7a,7b-                                                  bishomo-cis-17,18-                                                            methano-prostanoic                                                            acid                                                   610     580            9α,15-dihydroxy-2-ethyl-                                                cis-17,18-methano-                                                            prostanoic acid                                        611     581            9α,15-dihydroxy-10a-                                                    homo-cis-17,18-methano-                                                       prostanoic acid                                        612     582            9α,15-dihydroxy-2-meth-                                                 yl-cis-17,18-methano-                                                         prostanoic acid                                        613     583            9α,15-dihydroxy-3,3-                                                    dimethyl-cis-17,18-                                                           methano-prostanoic                                                            acid                                                   614     584            9α,15-dihydroxy-3-oxa-                                                  cis-17,18-methano-                                                            prostanoic acid                                        615     585            9α,15-dihydroxy-3-thia-                                                 cis-17,18-methano-                                                            Prostanoic acid                                        616     586            9α,15-dihydroxy-2-                                                      fluoro-cis-17,18-                                                             methano-prostanoic                                                            acid                                                   617     587            9α,15-dihydroxy-2-phen-                                                 yl-cis-17,18-methano-                                                         prostanoic acid                                        618     446A*          9α,15-dihydroxy-15-                                                     methyl-cis-17,18-                                                             methano-prostanoic acid                                619     446H*          9α,15-dihydroxy-15-                                                     methyl-3-oxa-cis-17,-                                                         18-methano-prostanoic                                                         acid                                                   620     446I*          9α,15-dihydroxy-15-                                                     methyl-3-thia-cis-                                                            17,18-methano-prostan-                                                        oic acid                                               621     446G*          9α,15-dihydroxy-15-                                                     methyl-3,3-dimethyl-                                                          cis-17,18-methano-                                                            prostanoic acid                                        622     446F*          9α,15-dihydroxy-15-                                                     methyl-2-methyl-cis-                                                          17,18-methano-pros-                                                           tanoic acid                                            623     446A**         9-oxo-15-hydroxy-15-                                                          methyl-cis-17,18-                                                             methano-prostanoic                                                            acid                                                   624     446C**         9-oxo-15-hydroxy-15-                                                          methyl-7a,7b-bishomo-                                                         cis-17,18-methano-                                                            prostanoic acid                                        625     446D**         9-oxo-15-hydroxy-15-                                                          methyl-2-ethyl-cis-                                                           17,18-methano-pros-                                                           tanoic acid                                            626     446G**         9-oxo-15-hydroxy-15-                                                          methyl-3,3-dimethyl-                                                          cis-17,18-methano-pros-                                                       tanoic acid                                            627     446H**         9-oxo-15-hydroxy-15-                                                          methyl-3-oxa-cis-17,-                                                         18-methano-prostanoic                                                         acid                                                   628     446I**         9-oxo-15-hydroxy-15-                                                          methyl-3-thia-cis-                                                            17,18-methano-pros-                                                           tanoic acid                                            ______________________________________                                         *9α,15dihydroxy product of this example only.                           **9oxo product of this example only.                                     

We claim:
 1. An optically active compound of the formula: ##STR13## or aracemic compound of that formula and the mirror image thereof wherein nis the integer 1 or 2; Y is a divalent radical selected from the groupconsisting of those of the formulae: ##STR14## p is an integer from 2 to6, inclusive; R₁ is an alkyl group having up to 3 carbon atoms; R₃ isselected from the group consisting of hydroxy and alkoxy having from oneto twelve carbon atoms; R₇ is selected from the group consisting ofhydrogen and a lower alkyl group having up to 3 carbon atoms; s is zeroor an integer from one to five inclusive; t is zero or one; and R isselected from the group consisting of cycloalkyl having from three tonine carbon atoms, cycloalkenyl having from five to nine carbon atoms,mono- or di-lower alkyl substituted cycloalkyl having from three toeight carbon atoms in the ring, and mono- or di-lower alkyl substitutedcycloalkenyl having from five to eight carbon atoms in the ring; withthe proviso that only one double bond or cyclopropyl group can beimmediately adjacent to C₁₅ ; and the pharmaceutically acceptablecationic salts thereof when R₃ is hydroxy.
 2. An optically activecompound according to claim 1, wherein Z, m, R₁, R₃, R₇, s and t are aspreviously defined; n is the integerl; Y is the divalent radical##STR15## p is the integer 3; and R is selected from the groupconsisting of cycloalkyl having from three to nine carbon atoms andcycloalkenyl having from five to nine carbon atoms.
 3. An opticallyactive compound according to claim 2, wherein R₁, R₃, s, t, n, Y, p, C₁₃-C₁₄ and R are as previously defined; and R₇ is selected from the groupconsisting of hydrogen and methyl.
 4. The racemic compound according toclaim 1,dl-9α,15-dihydroxy-20,20-(1,4-butano)-5-cis,13-trans-prostadienoic acid.5. The optically active compound according to claim 1, l-9α,15-dihydroxy-20,20-(1,4-butano)-5-cis,13-trans-prostadienoic acid. 6.The racemic compound according to claim 1,dl-9α,15-dihydroxy-20-cyclopentyl-5-cis,13-trans-prostadienoic acid. 7.The optically active compound according to claim 1,l-9α,15-dihydroxy-20-cyclopentyl-5-cis,13-trans-prostadienoic acid. 8.The racemic compound according to claim 1,dl-9α,15-dihydroxy-17,20-ethano-5-cis,13-trans-prostadienoic acid. 9.The optically active compound according to claim 1,l-9α,15-dihydroxy-17,20-ethano-5-cis,13-trans-prostadienoic acid. 10.The racemic compound according to claim 1,dl-9α,15-dihydroxy-19,20-(1,4-butano)-5-cis,13-trans-prostadienoic acid.11. The optically active compound according to claim 1,l-9α,15-dihydroxy-19,20-(1,4-butano)-5-cis,13-trans-prostadienoic acid.12. The racemic compound according to claim 1,dl-9α,15-dihydroxy-17,20-(1,3-propano)-5-cis,13-trans-prostadienoicacid.
 13. The optically active compound according to claim 1,l-9α,15-dihydroxy-17,20-(1,3-propano)-5-cis,13-trans-prostadienoic acid.14. The racemic compound according to claim 1,dl-9α,15-dihydroxy-20-methyl-17,20-ethano-5-cis,13-trans-prostadienoicacid.
 15. The optically active compound according to claim 1,l-9α,15-dihydroxy-20-methyl-17,20-ethano-5-cis,13-trans-prostadienoicacid.
 16. The racemic compound according to claim 1,dl-9α,15-dihydroxy-17-methyl-20-nor-16,18-ethano-5-cis,13-trans-prostadienoicacid.
 17. The optically active compound according to claim 1,l-9α,15-dihydroxy-17-methyl-20-nor-16,18-ethano-5-cis,13-trans-prostadienoicacid.
 18. The racemic compound according to claim 1,dl-9α,15-dihydroxy-16,20-methano-5-cis,13-trans-prostadienoic acid. 19.The optically active compound according to claim 1,l-9α,15-dihydroxy-16,20-methano-5-cis,13-trans-prostadienoic acid. 20.The racemic compound according to claim 1,dl-9α,15-dihydroxy-17,20-methano-5-cis,13-trans-prostadienoic acid. 21.The optically active compound according to claim 1,l-9α,15-dihydroxy-17,20-methano-5-cis,13-trans-prostadienoic acid. 22.The racemic compound according to claim 1,dl-9α,15-dihydroxy-16,19-ethano-5-cis,13-trans-prostadienoic acid. 23.The racemic compound according to claim 1,dl-9α,15-dihydroxy-16,20-ethano-5-cis,13-trans-prostadienoic acid. 24.The optically active compound according to claim 1,l-9α,15-dihydroxy-16,20-ethano-5-cis,13-trans-prostadienoic acid. 25.The racemic compound according to claim 1,dl-9α,15-dihydroxy-16-methyl-16,20-methano-5-cis,13-trans-prostadienoicacid.
 26. The racemic compound according to claim 1,dl-9α,15-dihydroxy-15-methyl-20-cyclopentyl-5-cis,13-trans-prostadienoicacid.
 27. The optically active compound according to claim 1,l-9α,15-dihydroxy-15-methyl-20-cyclopentyl-5-cis,13-trans-prostadienoicacid.
 28. The racemic compound according to claim 1,dl-9α,15-dihydroxy-15-methyl-19,20-(1,4-butano)-5-cis,13-trans-prostadienoicacid.
 29. The optically active compound according to claim 1,l-9α,15-dihydroxy-15-methyl-19,20-(1,4-butano)-5-cis,13-trans-prostadienoicacid.
 30. The racemic compound according to claim 1,dl-9α,15-dihydroxy-15-methyl-20-methyl-17,20-ethano-5-cis,13-trans-prostadienoicacid.
 31. The optically active compound according to claim 1,l-9α,15-dihydroxy-15-methyl-20-methyl-17,20-ethano-5-cis,13-trans-prostadienoicacid.
 32. The racemic compound according to claim 1,dl-9α,15-dihydroxy-15-methyl-17,20-methano-5-cis,13-trans-prostadienoicacid.
 33. The optically active compound according to claim 1,l-9α,15-dihydroxy-15-methyl-17,20-methano-5-cis,13-trans-prostadienoicacid.
 34. The racemic compound according to claim 1,dl-9α,15-dihydroxy-16-ethyl-19,20-(1,3-propano)-5-cis,13-trans-prostadienoicacid.
 35. The optically active compound according to claim 1,l-9α,15-dihydroxy-16,19-ethano-5-cis,13-trans-prostadienoic acid. 36.The racemic compound according to claim 1,dl-9α,15-dihydroxy-16,20-(1,3-propano)-5-cis,13-trans-prostadienoicacid.
 37. The optically active compound according to claim 1,l-9α,15-dihydroxy-16-methyl-16,20-methano-5-cis,13-trans-prostadienoicacid.
 38. An optically active compound of the formula: ##STR16## or aracemic compound of that formula and the mirror image thereof wherein nis the integer 1 or 2; p is an integer from 2 to 6 inclusive, R₁ is analkyl group having up to 3 carbon atoms; R₃ is selected from the groupconsisting of hydroxy and alkoxy having from one to twelve carbon atoms;R₇ is selected from the group consisting of hydrogen and a lower alkylgroup having up to 3 carbon atoms; s is zero or an integer from one tofive inclusive; t is zero or one; and R is selected from the groupconsisting of cycloalkyl having from three to nine carbon atoms,cycloalkenyl having from five to nine carbon atoms, mono- or di-loweralkyl substituted cycloalkyl having from three to eight carbon atoms inthe ring, and mono- or di-lower alkyl substituted cycloalkenyl havingfrom five to eight carbon atoms in the ring; with the proviso that onlyone double bond or cyclopropyl group can be immediately adjacent to C₁₅; and the pharmaceutically acceptable cationic salts thereof when R₃ ishydroxy.
 39. An optically active compound according to claim 38 whereinZ, m, R₁, R₃, R₇, s and t are as previously defined; n is the integer 1;p is the integer 3; and R is selected from the group consisting ofcycloalkyl having from three to nine carbon atoms and cycloalkenylhaving from five to nine carbon atoms.
 40. An optically active compoundaccording to claim 39, wherein m, R₁, R₃, s, t, n, C₁₃ -C₁₄ and R are aspreviously defined; Z is the divalent radical--(CH₂)_(m) --; and R₇ isselected from the group consisting of hydrogen and methyl.
 41. Anoptically active compound according to claim 39, wherein R₁, R₃, s, t,n, p, C₁₃ -C₁₄ and R are as previously defined; and R₇ is selected fromthe group consisting of hydrogen and methyl.
 42. The optically activecompound according to claim 38,l-9-oxo-15-hydroxy-16-ethyl-19,20-(1,3-propano)-5-cis,13-trans-prostadienoicacid.
 43. The racemic compound according to claim 38,dl-9-oxo-15-hydroxy-16,19-ethano-5-cis,13-trans-prostadienoic acid. 44.The optically active compound according to claim 38,l-9-oxo-15-hydroxy-16,20-(1,3-propano)-5-cis,13-trans-prostadienoicacid.
 45. The racemic compound according to claim 38,dl-9-oxo-15-hydroxy-16,20-methano-5-cis,13-trans-prostadienoic acid. 46.The optically active compound according to claim 38,l-9-oxo-15-hydroxy-15-methyl-18,20-ethano-5-cis,13-trans-prostadienoicacid.
 47. The compound according to claim 38,9-oxo-15-hydroxy-17,18-cis-methano-5-cis,13-trans-prostadienoic acid.